Companion to psychiatric studies Book 1

Companion to Psychiatric Studies

other psychiatric syndromes such as attention deficit hyperactiv- experienced as incentive salience, a potential link becomes
ity disorder (ADHD) impulsivity and the effects of dopamine- apparent (Kapur 2003).
releasing drugs such as Ritalin have been proposed (Williams
& Taylor 2004). Abnormal gaze learning in child development Social goals in animals and humans may employ the same
has also been studied from a TD perspective, motivated by TD neural mechanisms as learning about primary rewards
autism and Williams syndromes (Triesch et al 2006). All (O’Reilly et al 1999; Doya et al 2003; King-Casas et al 2005;
these theories are testable and some experimental work has Montague 2006). Recently, we have reported the presence of
already been done. a TD reward-learning signal in a social learning task involving
periods of social inclusion and exclusion (Kumar et al 2009).
Phasic aversive learning signals, tonic This finding helps to explain a link between hypothesized
signals, cognitive and social goals abnormal phasic reward learning signals and psychiatric illness,
as such illnesses are manifest substantially in the domain of
There is neuroimaging evidence that a phasic aversive learning social interaction. This view is consistent with the suggestion
signal, described by TD theory, exists in humans (Seymour that it may be possible to understand schizophrenia, and other
et al 2005, 2007). It has not yet been conclusively linked with psychiatric disorders such as major depression and addiction,
a specific neuronal type, but serotonin is considered by within a single framework.
Seymour and colleagues to be the best current candidate.
Abnormalities of phasic serotonergic activity may occur in Conclusion
major depression. This could account for characteristic
abnormalities in cognition (Huys 2007; Dayan & Huys 2008). It is often said that psychiatric disorders are unlikely to be
reducible to one neuromodulator, which of course is very
It is important to note that the ‘tonic’ (long timescale) likely. Whilst the above discussion has focused on dopamine
activity of dopamine (and perhaps other neuromodulators) (and behaviour), this has only been because of relatively more
has probably quite different effects compared with phasic work on this particular neurotransmitter. There is increasing
(‘fast’) activity; indeed the effects may sometimes be in oppo- understanding about information processing aspects of other
sition (Daw et al 2002; Niv et al 2007). Whilst long timescale neurotransmitters. For example, there is evidence that NA
measurements of dopamine in various psychiatric disorders encodes unexpected uncertainty and ACh expected uncertainty
have been reported by a number of groups, few studies have of the environment (Yu and Dayan 2005). Locus coeruleus-
investigated hypothesised abnormal phasic reward learning sig- noradrenaline function has been linked with adaptive alteration
nals in clinical populations, although this is changing. Long in behavioural exploration versus exploitation of environmen-
timescale measurements of dopamine would not be expected tal rewards (Aston-Jones & Cohen 2005). Serotonin may be
to detect phasic abnormalities. Furthermore, existing concepts linked to an aversive learning signal, perhaps as a ‘mirror
of phasic and tonic dopamine are an approximation, as there is image’ to dopamine and reward learning (Daw et al 2002).
evidence for dopamine having a range of functions whilst act- The theory of phasic dopamine, and its extension to incentive
ing over different timescales (Tobler et al 2007). salience theory and beyond, has clear experimental support.
It is a quantitative testable (falsifiable) theory with precise
It has been suggested by Montague and others that in definitions typical of the physical sciences, unlike older the-
humans, cognitive goal states are represented by the same pha- ories of brain function and non-evidence-based theories of
sic reward prediction error mechanisms evolved for learning mind. Several authors have hypothesized that phasic reward
about ‘simple’ primary rewards. According to Montague and and aversive learning signals may be abnormal in a variety
others, perhaps only in humans, explicit cognitive goals are of psychiatric disorders, and this could explain a number of
equivalent to US (O’Reilly et al 1999; Montague 2006). This clinical features. If such abnormality is found in reproducible
may be relevant clinically. There is robust evidence that anti- experimental work, it could lead to an incremental advance,
psychotics are effective in many psychotic illnesses. Clinical linking understanding of psychiatric disorders at biological,
understanding is limited to recognition of the importance of phenomenological and pharmacological levels (Kapur 2003).
D2 blockade, but how this translates into profound improve- Potentially, this could for example lead to new targets for drug
ments in emotional, cognitive and social functioning, from a action and assist in the identification of diagnostic biomarkers
biopsychosocial perspective, is unknown. However, if learning for illness. Only further work will clarify whether this
and pursuing cognitive goals requires the same phasic dopa- approach will be successful.
mine neural mechanisms as primary rewards, subjectively

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Shah, P.J., Ebmeier, K.P., Glabus, M.F., Schultz, W., 2006. Human neural learning
Goodwin, G., 1998. Cortical grey matter depends on reward prediction errors in the Zald, D.H., Kim, S.W., 1996. Anatomy and
reductions associated with treament-resistant blocking paradigm. J. Neurophysiol. 95, function of the orbital frontal cortex, I:
unipolar depression: Controlled magnetic 301–310. anatomy, neurocircuitary, and obsessive
resonance imaging study. Br. J. Psychiatry compulsive disorder. J. Neuropsychiatry
172, 527–532. Tobler, P.N., O’Doherty, J.P., Dolan, R.J., Clin. Neurosci. 8, 249–261.
Schultz, W., 2007. Reward value coding
Shallice, T., 1982. Specific impairments of distinct from risk attitude-related uncertainty Zola-Morgan, S., Squire, L.R., Alvarez-Royo, P.,
planning. Philos. Trans. R. Soc. Lond. B Biol. coding in human reward systems. J. Clower, R.P., 1991. Independence of
Sci. 298, 199–209. Neurophysiol. 97, 1621–1632. memory functions and emotional behavior:
separate contributions of the hippocampal
Smith, A.J., Li, M., Becker, S., Kapur, S., 2007. Triesch, J., Teuscher, C., Deak, G.O., formation and the amygdala. Hippocampus 1,
Linking animal models of psychosis to Carlson, E., 2006. Gaze following: why (not) 207–220.
computational models of dopamine function. learn it? Dev. Sci. 9, 125–147.
Neuropsychopharmacology 32, 54–66. Zola-Morgan, S., Squire, L.R., Amaral, D.G.,
Victor, M., Adams, R.D., Collins, G.H., 1971. 1986. Human amnesia and the medial
Squire, L.R., 1986. Mechanisms of memory. The Wernicke-Korsakoff syndrome, temporal region: enduring memory
Science 232, 1612–1619. Blackwell, Oxford. impairment following a bilateral lesion
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Squire, L.R., Moore, R.Y., 1979. Dorsal thalamic Vogt, B.A., Finch, D.M., Olson, C.R., 1992. J. Neurosci. 6, 2950–2967.
lesion in a noted case of human memory Functional heterogeneity in cingulate cortex:
dysfunction. Ann. Neurol. 6, 503–506. the anterior executive and posterior

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Neuropharmacology 3

Gordon Arbuthnott Marianela Garcia-Mun˜oz

Introduction The emphasis on studies of brain constituents in the early
phase of the development of neurochemistry was due in part
Neuropharmacological studies contribute extensively to the to the widely held, but erroneous, view that brain metabolism
evaluation of drug treatments in psychiatry and have provided was a very slow process. Subsequently, with the advent of iso-
useful insights into the neurobiology of mental illnesses. The topic tracer techniques, it became apparent that the brain had
fact that mental illnesses cannot be fully understood from a one of the highest metabolic rates of any tissue and that most
pharmacological perspective is in part attributed to their com- cerebral constituents are in a dynamic state, undergoing rapid
plexity but is to some extent related to the present stage of changes in association with changes in cerebral functioning.
development of neurobiology as a science. Molecular mechan- Knowledge of the chemical composition of the brain does
isms, especially those involving drug–receptor interaction and not, therefore, in itself, afford much understanding of cerebral
the control of genetic expression in the brain, form the focus function. Although the composition of the brain is altered sig-
of much current research in neuropharmacology. It is to be nificantly in a number of conditions (such as some of the
expected that as these studies progress even further the source inborn errors of lipid and amino acid metabolism), research
of symptoms in psychiatric disorders will be understood and on the neurochemistry of mental disorders over the past
rational treatment will improve, in the same way as under- 20 years concentrated on dynamic processes such as synthesis,
standing the cause of peripheral diseases such as diabetes turnover, release, uptake and transport of neurotransmitters.
made the symptoms accessible to rational therapy. Most present-day research focuses in addition on cellular and
network mechanisms contributing to brain activity, in genetic
Brain metabolism animal models of pathological states. Formidable practical
obstacles still exist, including the structural and functional
The first attempts to apply chemical methods to the study of complexity of the brain, its cellular heterogeneity and the
brain function were made several hundred years ago, and infor- enormous range of time-scales over which reactions can occur.
mation concerning the inorganic constituents of the brain was
obtained as early as 1719. With the development of suitable There are, for example, two major cell types in the brain –
chemical fractionation techniques in the 19th century, neurons and glia – and the difference in their functional roles is
detailed investigations of the organic constituents of neural tis- reflected in their very different chemical composition and
sue became feasible. Julius Schlossberger in his General and metabolic properties. However, even small samples of brain
Comparative Animal Chemistry devoted 135 of its 616 pages tissue will contain several types of neuron and glia, usually in
to the chemistry of neural tissues. This work stimulated a close juxtaposition, and it has been extremely difficult to sep-
number of more extensive studies of the nervous system by arate the contributions of each cell type to the metabolism of
the methods of organic chemistry, culminating in the most the tissue as a whole. A further complication is that the intra-
comprehensive of 19th century studies of brain composition: cellular concentrations of many chemicals within brain cells
Thudichum’s Treatise on the Chemical Constitution of the are not uniform. Each cell is composed of many types of
Brain, published in 1884 (see (McIlwain 1990). As early as organelle, each having a different chemical composition and
1833 attempts were being made to relate mental disorders to different metabolic properties. The existence of different met-
alterations in the chemical composition of the brain. abolic ‘pools’ within cells is known as compartmentation and is
particularly pronounced in the brain. Many brain constituents,
e.g. amino acids such as glutamate, are found in several
intracellular pools that differ in size and turnover rate.

ã 2010, Elsevier Ltd.
DOI: 10.1016/B978-0-7020-3137-3.00003-6

Companion to Psychiatric Studies

For these reasons classical biochemical methods for studying glucose, and in this the brain differs from other tissues which
metabolism (for example, the use of tissue slices and homoge- are able to utilise lipids and, to a lesser extent, protein. There
nates in vitro) can, when applied to the brain, yield data that is little storage of either lipid or glycogen. The glycogen con-
are extremely difficult to interpret. Although some of the pro- tent of brain is only 2–4 mmol/g and therefore the metabolism
blems can be overcome by use of such techniques as histochem- of the brain cannot be sustained by its carbohydrate reserves.
istry (to assist in precise localisation of substances), it has been Consequently, it is dependent on a constant blood-borne sup-
necessary to develop fractionation and analytical techniques to ply of glucose. Under normal conditions, the brain utilises
enable the study of the metabolism of different cell types in approximately 16–20 mmol of glucose per gram of brain per
isolation and the study of metabolism at the subcellular level. hour, and cessation of the blood supply of glucose and oxygen
The successful development of such methods, particularly results in loss of consciousness within less than 10 seconds
micromethods of single-cell analysis and functional optical (the time taken to consume the oxygen within the brain and
methods such as calcium imaging, has contributed greatly to its blood) and irreversible brain damage within minutes.
progress in neurochemistry. Recently neuroimaging techniques
have been used to elucidate the functional neuroanatomy and In nutritional studies, a commonly used index for estimat-
neurobiological processes underlying psychiatry disorders. ing the proportion of fat and carbohydrate being utilised
Magnetic resonance imaging (MRI) and functional MRI (fMRI) is the respiratory quotient (RQ; calculated by dividing the
can measure the result of metabolic changes in brain asso- volume of carbon dioxide produced by the volume of oxygen
ciated with different psychiatric conditions. Also, emerging consumed). The RQ for fat oxidation is 0.71 and the RQ for
genomic technologies are advancing our understanding of the carbohydrate oxidation is 1.00. The RQ calculated for the
contribution of genetic factors in these disorders. adult brain is 0.99. Under normal conditions, the amount of
oxygen consumed in the brain is equivalent to that of the glu-
The tasks performed by the cells of the brain are less con- cose removed from the blood (McIlwain & Bachelard 1985).
spicuously energy consuming than those of many other cells,
since they do not involve mechanical work, osmotic work or The normal arterial blood glucose concentration is approxi-
significant external secretory activity. There are, nevertheless, mately 80 mg/100 ml. When hypoglycaemia occurs, brain
many functions of brain cells that are energy intensive: the glucose consumption is reduced more than its oxygen utilisa-
maintenance of membrane potentials, active transport and tion and the total carbon dioxide produced by the brain can
the synthesis and axoplasmic transport of cellular materials. be increased to twice the basal level. Isotope experiments have
It is not surprising, therefore, that, with its organisational com- shown that this increased carbon dioxide production is due to
plexity and wide range of endergonic activities, the brain has a the oxidation of non-carbohydrate substrates, probably amino
high metabolic rate. Although it comprises a mere 2% of body acids and lipids. As a result, hypoglycaemia may be associated
weight it accounts for approximately 10% of the energy expen- with marked neurological manifestations, including convul-
diture and 20% of the oxygen consumption of the body at rest. sions, coma and death. In insulin-induced hypoglycaemia the
In children this percentage is even higher; the brain of a blood glucose concentration may fall as low as 8 mg/100 ml
5-year-old accounts for approximately 50% of the resting total and coma can result because, under these conditions, the
body oxygen consumption. The oxygen consumption of a typi- reduced production of ATP is inadequate for normal brain
cal neuron is between 10 and 100 times greater than that of a function. The pre-eminence of glucose as the substrate sup-
glial cell. Energy metabolism is not responsible for absolutely porting the energy-requiring activities of the mammalian brain
all the oxygen consumption of the brain, as the brain contains was first established over 50 years ago and remains unchal-
a variety of oxidases and hydroxylases that have a role in the lenged by more modern research (Auer 2004; Suh et al 2007).
synthesis and metabolism of a number of neurotransmitters.
However, important though these are, they account for a negli- A neuronal-glial functional metabolic coupling involving
gible proportion of the total oxygen consumption of the brain. glucose, lactate and pyruvate metabolism gives glial cells an
important role in neuronal metabolism (Mangia et al 2008).
As a consequence of its high energy requirement the brain It has been proposed that in the awake human brain the
is extremely sensitive to disturbances in the supply of its relative contribution of astrocytes to the total oxidative
energy sources, and many clinical conditions associated with metabolism is approximately 25% (Hertz et al 2007).
disturbances of brain function can often be traced back to a
deficiency in the production or utilisation of energy. Further- Although traditionally it has been considered that the brain
more, in view of the poor regenerative abilities of nerve cells, depends on glucose as its only energy source in vivo several
an energy deficiency of any duration can have long-term lines of evidence have shown that fructose, lactate, pyruvate,
implications for both functional and structural integrity. succinate and glutamate can also be oxidised by neurons
(Zielke et al 2007). Nonetheless glucose has an unimpeded
Primary energy sources entry by a set of diverse homeostatic mechanisms known
as the blood–brain barrier and rapidly reaches tissue levels
adequate for maintaining normal metabolism.

The brain, like the rest of the body, obtains its chemical energy Glucose metabolism
by the oxidation of foodstuffs. The energy derived from this
oxidation is stored in a utilisable form as high-energy phos- The manner in which the potential chemical energy of glucose
phate in molecules of adenosine triphosphate (ATP). The pri- is captured and utilised for the synthesis of ATP in the brain is
mary energy source of the central nervous system (CNS) is broadly similar to that in other tissues. It is achieved in three
main stages. First, glucose is converted to pyruvic acid by the

46

Neuropharmacology CHAPTER 3

glycolysis (Embden–Meyerhof) pathway in the cell cytoplasm. 1,6-diphosphate. Under aerobic conditions, however, the
Although this glycolytic pathway is the main pathway of glu- reduced coenzyme nicotinamide-adenine dinucleotide (NAD)
cose utilisation, the pentose phosphate pathway is also func- produced in the oxidation of glyceraldehyde phosphate is re-
tional and accounts for approximately 1% of the metabolic oxidised through the avoprotein cytochrome system, with
flux of glucose in human brain. Its primary role is to generate the formation of three ATP molecules. Further oxidation of
reduced coenzymes for use in biosynthetic pathways, but the each pyruvate molecule to carbon dioxide and water via the
pentose phosphates it produces are also important for local tricarboxylic acid cycle yields a further 15 molecules of ATP,
nucleotide synthesis as, in the adult, there is a restricted entry i.e. a further 30 molecules per molecule of glucose. This
of nucleotides from the blood to the brain. In the second stage ATP is produced by the re-oxidation of reduced NAD, NAD
of glucose breakdown, pyruvic acid is oxidised in the mito- phosphate (NADP) and flavin-adenine dinucleotide (FAD)
chondria to carbon dioxide via acetyl coenzyme A (acetyl- by the electron transport chain, but ATP is also produced by
CoA) and the Krebs (or tricarboxylic) acid cycle. In the third reaction of ADP and guanosine triphosphate (GTP) formed
stage, the electrons produced by the Krebs cycle enter the in the conversion of succinyl-CoA to succinate. Thus during
electron transport chain (avoprotein–cytochrome system) the complete oxidative breakdown of glucose to carbon diox-
where they are used in the reduction of oxygen. This process is ide and water there is a net production of 38 molecules of
coupled with the generation of ATP and is known as oxidative ATP. This represents a theoretical efficiency of 42% in captur-
phosphorylation. A summary of glucose metabolism in brain ing the energy latent in the glucose. However, in practice,
is shown schematically in Fig. 3.1. approximately 15% of brain glucose is converted from pyru-
vate to lactate and does not enter the Krebs cycle, and there-
ATP production fore the net gain of ATP is nearer 33 molecules per molecule
of glucose utilised (Clarke et al 1989).
During glycolysis, direct transfer of high-energy phosphate
from 1,3-diphosphoglyceric acid and phosphoenolpyruvate Regulation: metabolism in relation
to adenosine diphosphate (ADP) results in the formation of to functional state
two ATP molecules. Under anaerobic conditions, therefore,
there is a net synthesis of two ATP molecules as glucose Anaerobic metabolism of glucose, yielding as it does a mere
breaks into two triose molecules, and two ATP molecules are two molecules of ATP, cannot supply the energy requirements
used in the formation of glucose 6-phosphate and fructose of normal cerebral function, and as a result the brain is very

A D-Glucose
ATP
Pentose
phosphate ADP
pathway D-Glucose-6-P

D-Fructose-6-P
ATP

ADP
D-Fructose-1,6 diP

B Glucose Pyruvate

Dihydroxyacetone-P D-Glyceraldehyde-3-P

NAD+ 1,3-diP-glycerate Oxaloacetate α-Oxoglutarate
ADP COOH.CH2.CH2.CO.COOH
Lactate NADH + H+ Succinate Krebs
ATP COOH.CH2.CH2.COOH cycle Aspartate
3-P-glycerate

Alanine 2-P-glycerate Oxaloacetate

Pyruvate P-enolpyruvate Glutamate
ADP COOH.CH2.CH2.CH(NH2).COOH

CoA.SH NAD+

ATP CO2

CO2 NADH + H+ Succinic GABA
Acetyl CoA CoA.SH
Aspartate semialdehyde COOH.CH2.CH2.CH2.NH2

COOH.CH2.CH2.CHO

NADH + H+ Citrate Glutamate α-Oxoglutarate

Oxaloacetate

NAD+ Cisaconitate

Malate Isocitrate γ -Amino
NADP+
Fumarate
FADH + H+ CO2 NADP + H+ butyrate
(GABA)
FAD+
Succinate CoA.SH α-Oxoglutarate
CoA.SH

CO2 NAD+ Glutamate
ATP

GTP Succinyl CoA NADH + H+ ADP

GDP Glutamine

Fig. 3.1 Principal metabolic pathways of the brain (A) including the GABA shunt (B), a minor but important metabolic route in brain cells.

47

Companion to Psychiatric Studies

dependent on the efficient working of the Krebs cycle. This Aspartate and glutamate are glycogenic, since they are read-
dependence is reflected in the neurological dysfunction that ily and reversibly converted into oxaloacetate and a-oxogluta-
can ensue as a consequence of interference with its normal rate by transamination reactions. These reactions allow the
operation. Deficiency of thiamine, a cofactor in the conversion extensive synthesis of non-essential amino acids from Krebs
of pyruvate to acetyl-CoA, has profound effects on the CNS, cycle intermediates and aid in regulating the concentration of
as does a deficiency of niacin (required for NAD synthesis). metabolites entering this cycle. Another possible regulator of
However, carbohydrate metabolism in brain is relatively insen- the Krebs cycle in the CNS is the metabolic bypass around
sitive to a number of factors that have pronounced effects on the cycle from a-oxoglutarate to succinate – the GABA-shunt –
other organs. Thyroid hormones have been shown to have no which accounts for approximately 10% of the total glucose
effect on the cerebral respiration rate in the adult human, turnover (Fig. 3.1). Although this pathway is found at
although the development of the adult pattern of cerebral extremely low levels in some other tissues such as kidney,
glucose metabolism is retarded after neonatal thyroidectomy. heart and liver, it is by far most active in the brain. This is
There is even doubt whether insulin affects glucose transport due to the relatively high levels in the CNS of the enzyme
and utilisation in nervous tissue directly, although there have responsible for catalysing the decarboxylation of glutamate to
been reports that insulin is present in brain and does facilitate GABA. This enzyme, glutamate decarboxylase, in common
the entry of glucose in nervous tissues. with the transaminase enzyme, requires vitamin B6 phosphate
(pyridoxal phosphate) as a cofactor. The importance of these
Cerebral carbohydrate metabolism exhibits considerable interrelationships between the glutamate group of amino acids
flexibility to supply energy according to functional need. For and glucose metabolism is illustrated by the deleterious effects
example, during anaesthesia glucose utilisation is of the order of vitamin B6 deficiency. Glutamate decarboxylase and trans-
of 0.15 mmol kg–1 min–1 but during convulsions utilisation aminase inhibition caused by such a deficiency results in
can increase to more than 10 mmol kg–1 min–1. Such flexibility seizures. These seizures may be alleviated by the administra-
in the cerebral metabolic rate is possible because cerebral glu- tion of GABA, suggesting that they are primarily due to the
cose metabolism is regulated at a number of different levels: dysfunction of glutamate decarboxylase.
by changes in cerebral circulation; by changes in glucose trans-
port from the blood; and by changes in the rate of individual Metabolic imaging
enzyme reactions brought about by environmental influences
on the activity of key regulatory enzymes such as the glycolytic The powerful dependence of brain metabolism on glucose and
enzymes, hexokinase and phosphofructokinase. Energy output on oxygen supply has advantages for those who want to study
and oxygen consumption in the brain are associated with high the activity of areas of brain. Autoradiography, magnetic reso-
levels of enzyme activity in the Krebs cycle. The actual flux nance, magnetic resonance spectroscopy and functional
through the cycle depends on a number of factors. For exam- magnetic resonance have made possible the direct study of
ple the rate of glycolysis and acetyl-CoA production can ‘push’ both blood flow and glucose utilisation in animal and human
the cycle, while the activity of the pyruvate dehydrogenase brain. However, technical temporal and spatial resolution con-
complex controls the rate of pyruvate entering the cycle. In straints have made it impossible to obtain evidence of specific
addition, the local ADP level, which is the prime activator cell networks or the metabolic compartmentalisation between
of oxidative phosphorylation to which the cycle is linked, is different cell types. Results from these methods are presented
likewise important. Another factor contributing to the flexi- in greater detail in Chapter 4.
bility in metabolic rate is the fact that the substrate levels
found under normal physiological conditions are generally Pharmacokinetics
well below those required for maximum enzyme activities.
For example, under normal conditions only half of the brain
pyruvate dehydrogenase is active.

The g-aminobutyrate (GABA) shunt The effective concentration reached by any applied substance
in the relevant tissues depends upon its absorption, distribu-
The metabolism of the adult brain is characterised by a high tion, biotransformation and excretion, and these in turn
rate of incorporation of glucose carbon into free amino acids. depend upon its movement across cell membranes. This is
In this respect the brain differs markedly from other organs determined by a substance’s physical characteristics and the
such as the liver, kidney, lung, muscle and spleen. The expla- presence or absence of specific mechanisms to facilitate its
nation of this phenomenon is that the metabolism of certain passage across membranes. Passive movement of water-soluble
glucose metabolites is closely related to that of the ‘glutamate substances of low molecular weight – that is, less than 200 Da
group’ of amino acids. Members of this group (glutamate, (‘Daltons’) – is by filtration through aqueous channels, but
aspartate and GABA) have a special role in the CNS and these are too narrow (less than 0.4 nm) for most drugs, which
account for 75% of the free amino acids in the brain. They must pass through the cell membrane to enter a cell. Many
are found primarily in the grey matter and are associated with drugs are organic electrolytes and are weak acids or bases.
neuronal mitochondria. Glutamate, by its energy-dependent The extent to which a drug is ionised is determined by the
conversion to glutamine, plays an important role in the detoxi- pH of its solution and the dissociation constant (Kd) of the
fication of ammonia in the brain, and both glutamate and drug. The un-ionised portion is usually 104 times more lipid
GABA function physiologically as transmitters. soluble than the ionised portion and consequently much more

48

Neuropharmacology CHAPTER 3

Neurons The blood–brain barrier

CNS CSF The brain and CSF are separated from the blood by the blood–
ECF brain barrier, which regulates the movement of substances into
and out of the nervous system. It is represented structurally by
Cerebrovascular Choroid Venous Blood–brain the capillary endothelium of the brain, and functionally by
epithelium plexus sinuses barrier a complex set of active transport mechanisms. The cells of
cerebral vessel walls are so tightly bound together that diffu-
Plasma Free Tissue reservoirs sion between them is negligible, so they function as a single
Bound drug drug Free continuous sheet, behaving like a lipid membrane. Lipid-
soluble substances pass readily through this membrane,
Metabolites Bound whereas non-lipid-soluble substances and proteins enter the
brain much more slowly.
Absorption Excretion Biotransformation
In some specialised areas of brain the capillary endothelium is
Fig. 3.2 Pharmacokinetics of drug entry into the central nervous permeable – in the subfornical organ, the area postrema in the
system. CSF, cerebrospinal fluid; ECF, extracellular fluid. medulla, and in the region of the median eminence – and these
areas are often said to be ‘outside’ the blood–brain barrier.
soluble in the lipid bilayer of the cell membrane. The effective These high-permeability areas may allow transfer of compounds
concentration in brain is also controlled by active mechanisms such as peptides that cannot cross into brain elsewhere.
of both accumulation into, and elimination from, the cerebro-
spinal fluid (CSF). The pharmacokinetics of drug entry into The permeability of the blood–brain barrier to drugs (when
the CNS are complex and are summarised in Fig. 3.2. there is no specific mechanism of entry) is determined by the
general principles set out above. A ready guide to a drug’s
Absorption and distribution entry into the nervous system is provided by the ‘pH partition
hypothesis’. This states that the permeability of a cell
The passage of drugs into the brain is governed by the general membrane to a drug is proportional to that drug’s partition
principles of drug absorption and also by the specific ‘active’ coefficient, which is the ratio of the fractional concentrations
properties of the blood–brain barrier. One important general of un-ionised drug at equilibrium in two immiscible media —
principle is that drugs given in aqueous solution are absorbed lipid and water. The latter is usually measured as the optimal
more quickly than those dissolved in oils or given as solids. lipid/water partition coefficient. The pH of CSF can be regu-
Most drugs are given by mouth and the wide pH range lated independently of plasma pH because un-ionised carbon
encountered in the gastrointestinal tract influences absorption. dioxide passes across the blood–brain barrier much more read-
Oral ingestion is the most convenient and economical method ily than bicarbonate ions. CSF pH is usually 0.1 of a unit lower
of administration and, because drugs are absorbed relatively than plasma pH and, at equilibrium, concentrations of weak
slowly from the gut, is also relatively safe because adverse electrolytes may differ on either side of the blood–brain bar-
effects also develop slowly. Intravenous administration rapidly rier, so that weak bases tend to accumulate in the CSF
produces the desired plasma concentration of a drug but whereas weak acids tend to be excluded. The pH gradients
because the effects are immediate, adverse effects can be between plasma and CSF can, therefore, produce concentra-
serious or life threatening. Because the drug enters the blood- tion gradients at equilibrium for dissociated compounds.
stream directly, blood levels of the drug can rise above desired Figure 3.3 illustrates these principles by showing the relation-
therapeutic levels quickly. After a drug is absorbed into the ship between the uptake by the brain of radiolabelled sub-
bloodstream, it is distributed between extracellular and intra- stances and their lipid/water partition coefficients. When a
cellular fluids. At rest, distribution is determined by the drug has a partition coefficient greater than 0.03, it is almost
relative blood flow to the various regions of the body, so that completely cleared from the blood after carotid artery injection
highly perfused organs can reach peak concentrations within during a single brain passage.
the first few minutes. Except in the brain, capillary endothelial
membranes are highly permeable, allowing molecules as large Specific carrier transport systems unrelated to lipid affinity
as albumin (67 000 Da) to pass through intercellular aqueous are available for these substances (see Fig. 3.3). Amino acids,
channels. essential for brain function, are not usually synthesised in the
brain and so need to be transported from the blood. For exam-
The most immediate reservoir for drugs is formed by binding ple, the rate of entry of tryptophan into the brain is directly
to plasma proteins, particularly albumin. Binding is relatively dependent on the ratio of its plasma concentration to the
non-selective, so drugs compete for these binding sites. Drugs sum of the concentrations of phenylalanine, leucine, valine
can also accumulate in other reservoirs such as muscle, fat or and isoleucine. These other amino acids all compete with tryp-
bone, and as the plasma concentration falls, it may be released tophan for the same transport system. Amino acid transport
from body compartments, allowing its action to be sustained. mechanisms are stereospecific, preferring the laevo- to the
Many drugs are highly lipid soluble and so can be stored in body dextro-isomer. Active transport can operate in both directions
fat. In obese persons, this is an important drug reservoir. and against concentration gradients, either from the brain to
the blood or from the blood to the brain. This carrier, which
removes drugs and metabolites from brain, has many

49

Companion to Psychiatric Studies

200 Fig. 3.3 Percentage clearance of radiolabelled

Imipramine substances plotted against their lipid/water

100 Nicotine coefficients during a single brain passage
Ethanol following carotid arterial injection. Drugs with a
Procaine

Antipyrine Caffeine partition coefficient greater than about 0.03 show

14C Uptake Phenylalanine Heroin Methadone nearly complete clearance. The substances inside
3H Uptake × 100 Leucine Cyanide the box have very low lipid affinity but penetrate the
blood–brain barrier by virtue of specific carrier
D-Glucose Methionine

20 Arginine Dilantin transport systems. (After Oldendorf 1974 and Bradbury

Lysine Codeine Phenobarbital 1979.)

Ornithine

10

Ascorbic acid Method background level
Methotrexate 1 10
2 Acetylsalicylic acid Morphine

Benzylpenicillin
Cytosine 5-Iodo-2-deoxyurindine

arabinoside

0.0001 0.001 0.01 0.1 100

Olive oil
partition coefficient

H2O

properties in common with the acid transporter in the kidney, assumed, the rate of drug administration is therefore deter-
and may be a closely related mechanism. Some nervous system mined by its clearance. For most drugs used in psychiatry,
metabolites do not have specific mechanisms to clear them clearance is typically constant within the range of concentra-
from CSF, and so are only removed when CSF passes back tions seen in clinical practice. This arises because clearance
into the blood. mechanisms are not usually saturated and drug clearance is
observed to be a linear function of the drug’s blood concentra-
Biotransformation and excretion tion. A constant fraction of most drugs is cleared per unit
of time, and when this happens the drug is said to follow
Biotransformation of most drugs takes place in hepatic micro- first-order kinetics. When clearance systems for a drug are
somal enzyme systems, though other systems – including saturated, the pharmacokinetics of the drug becomes zero
plasma, gut, lung or kidney – may be involved. Lipid-soluble order and a constant amount of that drug is cleared per unit
drugs are more readily metabolised by hepatic microsomes of time. Clearance is calculated as the total volume of blood
because of their ease of entry into the cell. Considerable indi- (or other body fluid) from which a drug must be completely
vidual variation in biotransformation can be related to genetic removed, not as the total amount of drug removed. Total
factors, the effects of age, hepatic disease or induction of clearance represents the sum of clearance by each organ of
microsomal enzymes by other drugs or environmental agents. elimination (kidneys, liver, lung, etc.).
The processes of biotransformation can lead to activation or
inactivation of a drug and may involve numerous drug metabo- In some circumstances, clearance of a drug by a specific
lites. Unchanged drugs or their metabolites are removed from organ becomes a matter of clinical concern, for example the
the body by excretory organs such as the kidney or lung. Sub- renal elimination of lithium. Clinical investigation of renal
stances with high lipid solubility are not readily excreted until function of a patient on long-term lithium therapy might,
they have been metabolised to more polar compounds. The therefore, use an alternative definition of clearance. Clearance
kidneys remove most drugs or their metabolites by renal can be defined by the blood flow to the organ under investiga-
excretion involving glomerular filtration, active tubular secre- tion (Q), arterial concentration (CA) and venous concentration
tion and passive tubular reabsorption. Like all cell membranes, (CV). The difference between the products of blood flow and
kidney tubular cells are less permeable to the ionised portion blood concentration gives the clearance by an organ (CLorgan):
of drugs, and more permeable to lipid-soluble compounds.
Excretion of drugs in other body fluids is relatively unimpor- elimination ¼ QCAÀQCV ¼ QðCAÀCVÞ
tant, with the exception of breast milk.
CLorgan ¼ QðCAÀCVÞ=CA
Clearance
¼ QE
In psychiatric practice, the usual aim is to maintain the con-
centration of a drug within its presumed therapeutic range. The expression (CA–CV)/CA defines the extraction ratio (E)
‘Steady-state’ concentrations are attained when the rate of for a drug by a specific organ.
drug elimination (clearance) equals the rate of drug adminis-
tration. When complete bioavailability of a drug can be Some drugs show dose-dependent clearance that varies
with drug concentration in blood:

total blood clearance ¼ VM=ðKM þ CBÞ

where KM is the blood concentration at which 50% of
the maximum rate of elimination is reached (in units of

50

Neuropharmacology CHAPTER 3

mass/volume) and VM is the maximum rate of elimination (in synapses in the CNS. A major development in understanding
units of mass/time). Dosing schemes for these drugs can be the function of neurotransmitters in neural networks demon-
difficult. strated the feasibility of recording from slices of brain
in vitro (Yamamoto & McIlwain 1966). There followed other
Most psychotropic drugs are mainly cleared by the liver. important advances in recording techniques such as voltage
Hepatic clearance is largely determined by hepatic blood flow, clamp and patch clamp and a plethora of discoveries on spe-
i.e. the rate at which the drug can be transported to hepatic cific ion channels that led to the Nobel Prize in Medicine
sites of biotransformation and/or excretion in bile. Although awarded to Neher and Sakmann in 1991. Table 3.1 sum-
changes in drug binding to blood components and other tissues marises the properties of substances active at synapses.
(see Fig. 3.2) may influence hepatic or renal clearance, in pres-
ent circumstances, when a drug’s extraction ratio (E) is high, Neurotransmitters may open or close ion channels in the
changes in protein binding due to disease or competitive pro- pre- or post-synaptic neuronal membrane and can do this
cesses should have little effect on drug clearance. However, either directly or by activating adjacent proteins. Initially, it
when the extraction ratio is low, changes in protein binding was inferred that neurotransmitters caused a brief hyperpolar-
and intrahepatic functions will substantially alter drug clear- isation or depolarisation of the postsynaptic membrane. Now,
ance, but changes in hepatic blood flow will have little effect. it is known that they may have a much longer time-course of
Because a drug bound to blood proteins is not filtered and thus action, produced by them altering the properties of voltage-
not subject to active glomerular secretion and/or reabsorption, sensitive (or ‘voltage-gated’) ion channels involved in the regu-
renal clearance is substantially influenced by protein binding lation of neuronal excitability. There is a large family of ion
and thus by those diseases that affect protein binding. channel proteins, encoded in the human genome by more than
140 genes, amongst the most important of which are the
Neurotransmission families of channels for Naþ, Kþand Ca2þ. Apart from the
neurotransmitter receptors that possess intrinsic ion channels
Over 60 years ago, intracellular recording techniques estab- and generate current directly there are receptors that generate
lished beyond reasonable doubt the neurochemical nature of signalling molecules (or second messengers) that ultimately
synaptic transmission in most of the mammalian CNS. The impact the genetic machinery. The interaction of these signal-
small number of specialised electrical connections between ling pathways within the neuron is the subject of intense
central neurons is probably of little interest to neuropharma- research (Agnati et al 2008; Wayman et al 2008).
cology. Chemical neurotransmitters were shown to produce
inhibition or excitation of neurons by briefly and rapidly The central nervous system expresses a large number of
increasing neuronal membrane permeability to specific ions. voltage-dependent ion channels that form pores in the cell
Box 3.1 shows the ‘classical’ criteria for the identification of membrane comprising selective channels for Naþ, Kþ and
neurotransmitters that were once widely accepted. Later, Ca2þ. These channels contain six transmembrane segments
studies on single neurons identified noradrenaline (norepi- divided into two molecular domains – voltage-sensing seg-
nephrine), acetylcholine, serotonin, dopamine, g-aminobutyric ments and the pore segments themselves. The molecular
acid (GABA), glycine and glutamate as transmitters at differences in the structures of these two domains account

Table 3.1 Substances active in neuronal signalling

Box 3.1 Substance Properties Example

Criteria for identification of neurotransmitters Neurotransmitter A substance found in neuron type Acetylcholine
A, secreted from it and acting on
1. The transmitter must be shown to be present in the presynaptic target neuron type B
terminals of the synapse and in the neurons from which those
presynaptic terminals arise Neurohormone Peptide secretions from neurons Corticotropin-
directly into the blood that also act releasing
2. The transmitter must be synthesised in the presynaptic neuron on other neurons as factor (CRF)
3. The transmitter must be stored in an inactive form in the neurotransmitters

presynaptic terminal Neuromodulator A substance that influences Steroid
4. The transmitter must be released from the presynaptic nerve neuronal activity and originates hormones
from non-synaptic sites
concomitantly with presynaptic nerve activity
5. The effects of the putative neurotransmitter when applied Neuromediator Postsynaptic compounds that Cyclic adenosine
(second participate in generation of monophosphate
experimentally to the target cells must be identical to those of messenger) postsynaptic responses (cAMP)
the presynaptic pathway
6. The amount released by nervous activity (4) should be Neurotrophin Substances released by Nerve growth
comparable to that required to produce postsynaptic action (5) postsynaptic structures which factor
7. A method for control of the postsynaptic concentration which is ‘maintain’ presynaptic neuronal
capable of terminating the action of the transmitter is required, structure
e.g. a presynaptic uptake system or an enzymatic degradation at
the synapse

51

Companion to Psychiatric Studies

for most differences between voltage-gated ion channels. regulation of calcium currents near the resting membrane
Typically, the nomenclature system for these channels is based potential and during action potentials and have a wide distribu-
on the chemical symbol of the principal permeant through the tion in the central nervous system.
pore (i.e. Naþ, Kþ and Ca2þ) followed by the abbreviation of
the ligand, which in the case of voltage-dependent ion channels Functional auxiliary subunits associated with Ca2þ channels
is ‘v’ for voltage (other channels bind Ca2þ and use ‘Ca2þ’ as form another set of subunits (Cava2d, Cavb and Cavg) which
part of the abbreviation). Some more recent nomenclatures seem to enhance membrane trafficking and modulate voltage-
also include the gene subfamilies. The complexity is consider- dependent gating.
able and anyone particularly interested in voltage-dependent
ion channel nomenclature should consult the International Calcium-activated potassium channels
Union of Basic and Clinical Pharmacology official database
(http://www.iuphar.org). The Ca2þ-activated Kþ current – i.e. KCa – channels have dis-
tinct affinities for Ca2þ which give rise to the voltage- and
Potassium channels Ca2þ activated large conductance Kþ channel (BKCa) and the
Ca2þ activated small conductance Kþ channel (SKCa). BKCa
Potassium channels are highly diversified in terms of both channels, whose Ca2þ sensitivity is regulated by protein kinase
their distribution on the neuron and the characteristics of CK2 and protein phosphatase 2A, modulate excitability and
the currents generated (Gutman et al 2005). Kv2 forms the contribute to synaptic plasticity, their currents contributing
delayed rectifier of the Kv channels (cf. Chapter 11). to repolarisation of the action potential, mediation of the fast
The Kv3 family members have unique characteristics like fast phase of the afterpolarisation following an action potential,
activation and deactivation rates, properties that allow neurons shaping dendritic Ca2þ spikes and influencing neurotransmit-
to fire action potentials in close succession. The Kv4 family ter release. SKCa channels are not dependent on voltage and
forms the transient A-type current, while Kv4 channels inter- are not co-assembled with Cav channels. They have a high sen-
act with a calcium-binding protein, KChIP. The Kv7 channels sitivity for Ca2þ and are opened by elevations of internal Ca2þ
underlie the slowly activating, non-inactivating M current from various sources.
that suppresses neuronal firing in many types of neurons.
Reduction of Kv7 channel activity as a result of genetic muta- Other molecules (i.e. ATP, cAMP or protein subunits) can
tion results in various human diseases due to cell hyperexcit- open Kþ channels. KATP channels, for example, are activated
ability, including epilepsy, cardiac arrhythmias and deafness. by decreased ATP/ADP ratios. These channels are found in
Activation of Kv7 channels limits the electrical activity of the nigrostriatal dopamine neurons in high concentrations.
dopaminergic and serotonergic neurons (Hansen et al 2008). Both neuroprotective or neurotoxic effects have been pro-
A novel action of Kv7 channels could translate into future posed for the action of KATP channels in these neurons since
treatment of diseases characterised by overactivity of dopami- their activation leads to prolonged hyperpolarisation and
nergic and serotonergic neurons. decreased cell activity (Wang et al 2008).

Calcium channels Calcium plays a crucial role in neurotransmitter release,
which represents the ‘final common pathway’ of all neuronal
Multiple types of Ca2þ channel exist in neurons, the distinc- functions. Figure 3.4 summarises the cellular processes
tions playing an important part in understanding neuronal involved, which are again highly complex. The presynaptic ter-
function and its modification by drugs and neurotransmitters. minal contains a variety of proteins which contribute to neuro-
transmitter release, calcium-calmodulin protein kinase II
Ca2þ channels are composed of several subunits for channel (CaMKII) and the BKCa channel being two important proteins
regulation. There are however many types of Ca2þ currents in the process. Presynaptic CaMKII is activated by Ca2þ and
(e.g. L-type; N-type; P/Q-type, etc) for which an alphabetical calmodulin associated with the outer surface of the synaptic
nomenclature was developed from their physiological proper- vesicle and regulates neurotransmitter release and synaptic
ties, before their molecular genetics was known. The channels plasticity by itself acting through different proteins. Synapsin
themselves have been divided into three subfamilies, relating I is associated with synaptic vesicles and with the cytoskeletal
to the electrophysiological currents they support. The Cav1 protein actin by an action regulated by CaMKII. A leading
(or L-type) channel has four subfamilies, two of which hypothesis is that synapsin I attaches synaptic vesicles to the
(Cav1.2 and Cav1.3) are expressed in the central nervous sys- cytoskeleton by associating with actin and synaptic vesicles
tem. The Cav2 subfamily (Cav2.1, Cav2.2, Cav2.3) conduct and this link is broken by the action of CaMKII. The BKCa
the P/Q-type, N-type and R-type Ca2þ currents, respectively channel is a negative regulator of synaptic transmission. It has
(Catterall 2000). By regulating neurotransmitter release, been proposed that CaMKII may also modulate this channel.
Cav2 channels are involved in short-term synaptic plasticity Neurotransmitter release is triggered by Ca2þ entering through
in response to bursts of action potentials. Knowledge about Cav channels, of which Cav2.1 appears to be the primary one
these channels allows the study of their participation in human implicated. Ryanodine receptors (RyR) are Ca2þ releasing
disease – e.g. mis-sense mutations of Cav2.1 cause familial channels in the endoplasmic reticulum membrane, of which
hemiplegic migraine, a rare inherited form of migraine. The there are three isoforms (RyR1-3). In general, RyR receptors
Cav3 subfamily (T-type) underlies transient currents that promote spontaneous action potential independent exocytosis,
activate subthreshold membrane potentials crucial for the enhance neurotransmitter release and contribute to synaptic
plasticity. Synaptic vesicles are secreted only at active zones
and after docking. The ability to dock depends on the

52

Neuropharmacology CHAPTER 3

Budding ADP + PH+ ATP
NT

NT ADP + PH+ ATP

Other Kiss and run NT uptake Vesicle acidification
factors Full fusion

ATP Ca2+

Docking Priming Fusion pore Fusion pore New vesicle Endocytosis
opens dilates formation

Fig. 3.4 Neurotransmitter vesicles bud off from the endoplasmic reticulum, are filled with transmitter, and dock at a
release site on the presynaptic membrane. Docked vesicles undergo a reversible process called priming and are then
ready to release their contents either by generation of a fusion pore or by complete fusion with the outer cell membrane
in response to the influx of calcium that follows terminal depolarisation. The membrane recycling is achieved by the
formation of clathrin-coated pits that bud off to become vesicles that can be refilled or recycled through the endosome.
Detailed discussion in Chapman 2008.

composition of the vesicle membrane and the active zone. pathways mediate some rapid aspects of synaptic transmission,
Synaptotagmin is an integral membrane protein of synaptic like modulation of ion channel opening and closing and some
vesicles which appears to sense Ca2þ for the fast release of long-term effects on neurotransmitter synthesis, storage,
neurotransmitters. Synaptic vesicles are coated on their cyto- release and neuronal growth, to mention a few. Alterations in
plasmic face by N-ethylmaleimide-sensitive factor attach- the neurotransmitter receptors resulting from prolonged expo-
ment protein (SNAP) receptor (SNARE) proteins. SNARE sure to receptor agonists or antagonists – desensitisaton and
proteins, which include VAMP (synaptobrevin), syntaxin sensitisation of receptor function – are mediated by the action
and SNAP-25, aid synaptic vesicle fusion and may be phos- of second messengers. Cyclic nucleotide second messengers,
phorylated by CaMKII. adenosine 3’-5’-cyclic monophosphate (cAMP) and cyclic gua-
nosine monophosphate (cGMP), were among the first to be
Sodium channels identified. cAMP and cAMP response element binding protein
(CREB), a transcription factor that mediates the effects of
The Nav channel was the first voltage-dependent ion channel cAMP on gene expression, have been demonstrated to play
to be cloned. Currently Nav1 is the only subfamily within a critical role in the formation of neuronal plastic changes
the Nav. An auxiliary b subunit glycoprotein is associated associated with learning and memory, the control of receptor
with the Nav channel. Nav channels within the central nervous sensitivity, and other long-term neuronal changes resulting
system and heart contain Navb1 to Navb4 subunits. The mus- from drug addiction.
cle expresses only the Navb1 subunit. The Nav1 channels initi-
ate and propagate action potentials in virtually all mammalian An example of the importance of intracellular signalling
central neurons. pathways for psychiatry comes from studies attempting to
clarify the role of lithium in neuronal function. Although
Intracellular signalling pathways lithium, a drug used in the treatment of bipolar disorder, is
effective in clinical use, little was known until recently about
Extracellular molecules, by acting on membrane receptors, how it impacts neuronal molecular function.
can induce intracellular changes that ultimately generate a dif-
fusable molecule (second messenger), which can in turn acti- Two signal transduction pathways have been linked to intra-
vate intracellular signalling pathways. Intracellular signalling cellular effects of lithium: one mediated by inositol (1,4,5)-
trisphosphate [Ins(1,4,5)P3] signalling and the other mediated
by glycogen synthase kinase 3b (GSK-3b) (Quiroz et al 2004).
The turnover of inositol-containing phospholipids results in

53

Companion to Psychiatric Studies

the formation of second messengers, inositol 1,4,5-triphos- Box 3.2
phate and diaglycerol (DAG), which are capable of mobilising
intracellular Ca2þ and activating protein kinase C (PKC), Criteria for identification of receptors
respectively. PKC activation in turn potentiates neurotransmit-
ter release. These events are important components of the reg- • ‘Possible’: Radioligand binding sites
ulation of neurotransmission and are affected by lithium. PKC — Saturability and reversibility of radioligand binding
activation by phorbol esters mimics the action of DAG and is — Homogeneous population of sites
blocked by lithium. Since PKC activation also potentiates sero-
tonin and noradrenaline release, this effect of lithium at thera- — Regional and species variation
peutically relevant concentrations suggests a possible mode of
its action in the treatment of mania and prophylaxis of manic– — Pharmacological properties
depressive illness (Wang & Friedman 1989). • ‘Probable’: Functional correlates

Glycogen synthase kinase 3 (GSK-3) is an enzyme which — Identification of special messenger links
was first discovered based on its ability to phosphorylate
and inactivate the enzyme glycogen synthase, an action that — Delineation of physiological effects on membranes
leads to a decrease in the synthesis of glycogen. Lithium
inhibits GSK-3 (Stambolic et al 1996). GSK-3 phosphorylates — Behavioural or other models of action
and inactivates many transcription factors, thereby modulating • ‘Definite’: Structural identification
the function of proteins, including: Wnt proteins (regulation
of cell-to-cell interactions during embryogenesis); b-catenin — Unique amino acid sequence
(an integral component of Wnt signalling pathway); and
microtubule-associated protein (cytoskeleton) and tau pro- — Cloned sequences mimic actions of natural receptor
teins (cytoskeleton), hyperphosphorylation of which leads to
Alzherimer’s ‘tangles’. GSK-3 also phosphorylates two impor- After Peroutka (1988).
tant transcription factors: activator protein-1 (jun) and CREB.
binding is usually reversible. The physical configuration of
It is likely that lithium exerts its therapeutic influence by the receptor largely determines the structural requirements
its action on the neuronal genetic machinery but we are still of a drug designed to interact with that receptor. Several clin-
far from understanding its precise mode of action (Williams ically important drugs in psychiatry have been developed from
& Harwood 2000; Seelan et al 2008). This issue is discussed deliberate chemical changes to the structure of the endoge-
again within a clinical context in Chapter 11. nous ligand – i.e. physiological agonists. (Additionally, small
changes of structure can alter the pharmacokinetic properties
Pharmacodynamics of drugs.) Neural receptor mechanisms include recognition
of the neurotransmitter (usually by a cell surface protein)
Pharmacodynamics concerns the mechanism of action of drugs. and transduction of the message into alterations of cellular
Knowledge of drug pharmacodynamics in psychiatry is basic activity that may involve changes in ionic permeability and
to their clinical use. Studies of drug action aim to identify the formation of intracellular second messengers, such as cyclic
chemical and physical interactions between drug and neuron adenosine monophosphate (cAMP), IP3 or immediate early
and a proper understanding of the temporal order and scale of genes (IEG).
drug–neuron interactions provides the basis for understanding
drug effects. It can be used to help design improved drugs Drugs that bind to receptors and initiate a response in
and potentially may provide information of relevance to under- neuro-effector tissue are agonists. Drugs that produce a maxi-
standing neurobiological components of psychiatric disease. mal response are full agonists, and those producing less than
the maximal response are partial agonists. Drugs that have
Receptors no intrinsic pharmacological activity but produce effects by
preventing an agonist initiating a response are antagonists.
Receptors are conceptualised as large, functional molecules Some antagonists can produce a partial pharmacological
that, in response to binding with endogenous or pharma- response (‘partial agonist activity’) at receptor binding sites
cological molecules (ligands), change cellular activity. The where they compete with endogenous ligands. Some drugs
physical and chemical features of receptor molecules may vary combine both agonist and antagonist properties as mixed
substantially. Some are protein constituents of the cellular agonist–antagonists, and understanding these properties may
membrane, others are proteins that are important in the main- have therapeutic potential. For example, a mixed opiate
tenance of subcellular architecture and some are intracellular agonist–antagonist might have the advantage of providing relief
enzymes or proteins concerned with cellular transport. of pain with much less risk of addiction than a full agonist such
Box 3.2 lists some of the major methods for identification of as morphine. Pharmacological antagonism is distinct from
receptors in nervous tissue. Interactions between drugs and physiological antagonism produced by substances initiating
receptors are of multiple types and include covalent, ionic, an opposing response in neuroeffector tissue. For example,
hydrophobic and van der Waals binding. Covalent binding noradrenaline can act as a physiological antagonist of acetyl-
tends to be of long duration, while non-covalent high-affinity choline but has negligible action at acetylcholine receptors.

Classical receptor theory assumes that the effect of a drug
is proportional to the number of receptors with which
that drug interacts. The ease with which a drug attaches to a
receptor is termed the affinity of the drug for that receptor.
Receptors for neurotransmitters are components of the neural
membrane. They are able to recognise specific neurotrans-
mitters and produce physiological responses in neuroeffector

54

Neuropharmacology CHAPTER 3

tissues. Receptors can, therefore, be defined both in terms of Table 3.2 Examples of ‘superfamilies’ of receptors
their ability to recognise specific ligands and by the physiolog-
ical responses they initiate. Superfamily Neuroreceptor ion channel

Receptor sensitivity G-protein-coupled receptors Visual pigments
Adrenergic
Drug–receptor interactions may be modified by changes in Muscarinic cholinergic
receptor sensitivity, this being influenced by complex regu- Serotonergic
latory and homeostatic factors. When receptor sensitivity
changes, the same concentration of a drug will produce a Ligand-gated ion channel receptors Nicotinic cholinergic
greater or lesser physiological response. Changes in sensitivity GABAA
occur, for example, when, after prolonged stimulation of cells Glycine
by agonists, the cell becomes refractory to further stimulation. Glutamate
This is also termed ‘desensitisation’ or ‘downregulation’.
Underlying mechanisms of desensitisation may involve recep- Tyrosine-kinase-linked receptors NGF
tor changes (e.g. phosphorylation), or the receptor may be Neurotrophins
concealed within the cell so that it is no longer exposed to BDNF
the ligand. Long-term desensitisation may involve negative- CNTF
feedback mechanisms that inhibit new receptor synthesis or GDNF
cause a structurally modified receptor to be synthesised. In
the nicotinic receptor, desensitisation involves at least two dis- BDNF, brain-derived neurotrophic factor; CNTF, ciliary neutrophic factor; GDNF, glial
tinct ‘closed’ states, both of which display a higher affinity for cell-derived neurotrophic factor; NGF, nerve growth factor.
acetylcholine than does the resting (or ‘active’) conformation.
Structural studies show that a specific segment of the G-protein-coupled receptors
lumen-facing part of the ion channel is crucial in the process
of desensitisation in response to prolonged agonist exposure G proteins are cellular proteins with many functions whose
(Revah et al 1991). This segment of the ionic channel is highly name derives from the fact that they bind the guanine nucleo-
conserved in other receptor types (e.g. GABAA and glycine tides, guanosine triphosphate (GTP) and guanosine diphos-
receptors) where it may play a similar role. phate (GDP), and possess intrinsic GTPase activity. These
proteins link cell surface receptors to a variety of enzymes
Supersensitivity (‘upregulation’ or ‘hypersensitivity’) was and regulate second messengers or directly couple to ion chan-
first described after removal of the presynaptic element but nels (Fig. 3.5). By far the largest known class of receptor
often follows prolonged receptor blockade. This may involve (summarised in Table 3.3) functions by stimulating membrane-
synthesis of new receptors so that an increased number of bound G proteins. Members of the family are composed
receptors are exposed on the cell surface to their physiological of three homologous subunits: a, b and g. Different types of
ligands. In the case of supersensitivity following the destruc-
tion of the presynaptic terminal, the loss of mechanisms that α-GDP
terminate transmitter action (e.g. uptake, enzymatic degrada-
tion) also contribute to the increase in response to agonist.

Receptor families α-GDP Pi
βα
Historically, there has been considerable debate about criteria
for the characterisation of receptor subtypes. Practically, the βγ GDP
identification of new receptor types has quickly followed α-GTP
the development of specific, potent agonists and/or antago-
nists that selectively bind to the new receptor (see Box 3.2). α
Molecular, biochemical and physiological techniques indicate βγ
the existence of several ‘superfamilies’ (probably less than 10)
of receptor macromolecules (Table 3.2). Molecular biological GTP
techniques have provided the best classification of subtypes
within receptor superfamilies. Progress in this field has consis- Fig. 3.5 The G protein cycle of activation in transmembrane
tently led to revision of classification systems based on bio- signalling. The abg complex is stable only with GDP bound to the a
chemical and physiological studies. Within each superfamily subunit. Binding GTP to the a subunit dissociates the complex, which
of receptor types there can be considerable structural diversity can only reassociate after dephosphorylation of GTP to GDP. The free
of their endogenous ligands. Receptors within each receptor bg complex acts on many cellular subsystems, including ion channels
family, however, have many structural similarities with other and intracellular signalling pathways. (After Sternweis & Pang 1990.)
members of the same family and share common mechanisms
of signal propagation.

55

Companion to Psychiatric Studies

Table 3.3 Neurotransmitter ligands acting through G-protein- Extracellular
coupled receptors*

Ligand Receptor subtype Receptor family 2 3
subtype 4
1 5 6 7

Acetylcholine Muscarinic 3 Rhodopsin-a

Adrenaline 1A, 2A, B1, B2 Rhodopsin-a A
Rhodopsin-g Intracellular
Angiotensin AGTRA1 Rhodopsin-a
Cannabinoids CB1 Rhodopsin-d CHO
Corticopropin-releasing H CRHR1, CRHR2, CRHR3 Rhodopsin-a N 76
Dopamine D1, D2 Glutamate
Gamma amino butyric acid GABAB1, GABAB2 Glutamate 15
Glutamic acid mGlu1, mGlu2, mGlu8 Rhodopsin-b 234
Gonadotropin-releasing GnRH1
hormone Rhodopsin-d B
Intracellular
Growth hormone-releasing GHRHR
hormone

Histamine H1R, H2R, H3R, H4R Rhodopsin-a Fig. 3.6 (A) The peptide chains of the b-adrenergic receptor (and
Neuropeptide Y Y1, Y2 Rhodopsin-b G-protein-coupled receptors in general) are assumed to span the
Opioids d, k, m Rhodopsin-g extracellular membrane as shown. (B) A three-dimensional array of
the seven membrane-spanning helices shown in (A).

Oxytocin OT Rhodopsin-b the G-protein-coupled receptors is found largely in the
membrane-spanning regions. The cytoplasmic regions and
Serotonin 1A,1D, 2A Rhodopsin-a loops between spans 5 and 6 show minimal sequence homol-
ogy (Ross 1989). Neurotransmitter and hormonal ligands bind
Somatostatin SSTR2, SSTR5 Rhodopsin-g to G-protein-coupled receptors in the pocket formed by the
seven helices. The G proteins are located on the intracellular
Vasoactive intestinal VIP1, VIP2 Rhodopsin-d surface of the plasma membrane, and it is likely that part of
peptide the receptor which regulates G proteins is also on the intracel-
lular face. Binding of the ligand to the extracellular part of the
*For progress on receptor nomenclature and drug classification visit the International receptor distorts the binding site to an extent sufficient to
Union of Basic and Clinical Pharmacology homepage: http://www.iuphar-db.org/ alter the cytoplasmic part of the receptor and to transform it
from its passive to active state. The cytoplasmic loop between
G protein contain different a subunits which confer distinct spans 5 and 6 is probably the G-protein regulation site as
G-protein regulation is sensitive to mutations in this region.
functional activities. In the structural arrangement between
Most of the G-protein-coupled receptors are grouped in
the G protein, its subunits and the associated receptor, the five families under the acronym ‘GRAFS’, which stands for
Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secre-
a subunit plays an important role, having two identifiable tin receptors (Lagerstrom & Schioth 2008). The glutamate
family consists of 22 receptor proteins: eight metabotropic
domains – one which contains the GTPase activity, another glutamate receptors, two subunits of the GABAB receptor,
the Ca2þ-sensing receptor, the sweet and umani taste recep-
the GTP-binding site. Nine types of G proteins have been tors, the GPRC6A receptor, which binds L-a basic aminoacids
(arginine, lysine and ornithine), and seven receptors termed
identified (Gt, Gs, Gi, Go, Golf, Ggust, Gz, Gq and G11–19 ), ‘orphan’ since no endogenous ligand has been identified so
divided in turn into four main groups: Gs (Gas1–4 and Gaolf), far. The rhodopsin receptor family is the largest family of
Gi (Gai1–3, Gao1–2, Gat1–2, Gagust, GaZ), Gq (Gaq, Ga11, receptors with approximately 670 receptor proteins. This
Ga14, Ga15, Ga16) and G12 (Ga12–13). The Gs family stimu- family is subdivided into four groups: a, b, g and d~. The
lates adenylyl cyclase; the Gi family can inhibit adenylyl a-group includes cholinergic muscarinic receptors, prostanoid
cyclase, activate a certain type of Kþ channel, inhibit voltage- receptors and receptors binding histamine, dopamine, seroto-
gated Ca2þ channels, activate the MAP-kinase pathway or nin, adrenaline and cannabinoids. These receptors are tar-
gets for drugs such as antihistamines, antacids, drugs for
activate phosphodiesterases; the Gq family activates the phos-
phoinositide-specific phospholipase C which catalyses the

hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2);
the G12 family activates a group of proteins termed Rho-

GEFs (guanine nucelotide exchange factors). Receptors cou-

pled to G proteins have similar structures that include seven

transmembrane helices (Fig. 3.6). Sequence homology among

56

Neuropharmacology CHAPTER 3

regulation of heart rate and blood pressure, and antipsychotics. A δ γα β
Prostanoid receptors are targeted for the treatment of glau- H3N+
coma and ulcers and the cannabinoids for the treatment of ACh
obesity. Ligands for the b-group of the Rhodopsin family
are mainly peptides, such as neuropeptide Y, endothelin, Ca2+
gonadotropin-releasing hormone and oxytocin. The g-group
includes receptors for peptides and lipid-like compounds. Ca2+
This family comprises among others three opioid receptors,
somatostatin receptors 2 and 5 and angiotensin receptor 1, PO4 C O
which are targets for drugs involved in the treatment of O
inflammatory diseases, pain and addiction. The d-group con-
tains thrombin receptors, glycoprotein-binding receptors, PO4
nucleotide-binding receptors and olfactory receptors.
Cytoskeleton
The adhesion receptor family is the second largest family,
with 33 receptor proteins. This family has a sequence simi- Bγ α
larity between the transmembrane regions of the adhesion
G-protein-coupled receptors and the secretin receptors but δβ
its long N-terminus sets it as a different group of receptors.
Besides, the adhesion receptors bind extracellular matrix α
molecules whereas secretin receptors bind neuropeptides. So
far only three ligands have been identified for these receptors. Fig. 3.7 Model of the ion channel of the nicotinic acetylcholine
The frizzled/taste 2 family is formed by the frizzled receptors receptor. (A) Longitudinal section (ACh, acetylcholine). (B) Cross-
originally identified with important functions in Drosophila section of the narrowest part of the channel. (After Guy & Hucho 1987.)
development and later implicated in cancer development.
Research on the bitter taste receptors gave rise to the taste receptor families. The pentameric receptor family comprises
2 receptors. The human genome contains 25 functional genes the nicotinic acetylcholine receptor, the subtype 3 serotonin
for these receptors but many of them remain orphans. receptor, a zinc-activated channel and the GABAA receptor.
The tetrameric ionotropic glutamate receptors are subdivided
The secretin receptor family contains 15 receptor proteins into N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-
which include the secretin receptor, calcitonin and calcitonin- methyl-4-isoxazole propionic acid (AMPA) and the kainic acid
like receptors, the corticopropin-releasing hormone receptors, receptor subfamilies (GluK1, GluK2, GluK3, GluK4 and
the glucagon receptor and the glucagon-like peptide recep- GluK5 – previously known as GluR5–7 and KA1 and KA2;
tors, the gastric inhibitory polypeptide receptor, the growth Jane et al 2009). The trimer receptor family is formed by
hormone-releasing receptor, the adenylate cyclase-activating seven identified P2X purinergic receptor proteins.
polypeptide receptor, the parathyroid hormone receptors, and
the vasoactive intestinal peptide receptor. This family has Steroid and thyroid hormone-like receptors
been targeted for drug developments for the treatment of
hypercalcaemia, hypoglycaemia and osteoporosis. Receptors for steroids (estrogens, androgens, progestins, gluco-
corticoids, mineralocorticoids and vitamin D) and thyroid
The G-protein-coupled receptors were for a long time con- hormones (thyroxine (T4) and 3,5,3,0-tri-iodothyronine (T3))
sidered to be unique among integral membrane proteins are all part of a single family of receptor macromolecules
because they were monomeric (i.e. small G proteins). How- (Evans 1988). They are highly ligand-specific phosphoproteins,
ever, more and more data indicate that G-protein-coupled so that each type mediates the effect of a specific hormone
receptors can form oligomers, either homo-oligomers (identical or other ligand on its ‘target’ gene. They are located intra-
subunits) or hetero-oligomers (distinct subunits). Heterodimer cellularly and comprise a ligand-binding domain and a part that
G-protein-coupled receptors include the glutamate (mGlu couples the receptor to an enhancer that unwinds the DNA or
receptors) and the GABAB receptor (Pin et al 2007). to another protein transcription factor, such as fos-jun com-
plex or adaptor protein 1. In the better-understood sequence
Ligand-gated ion channels of events, when the hormone binds to the receptor a con-
formational change occurs which exposes the DNA-binding
Many of the best-known transmitter actions are mediated
by this superfamily of receptors (Collingridge et al 2009).
Acetylcholine acts at the neuromuscular junction on just such
a receptor and the major receptors for glutamate and for
GABA in brain are also of this type. The nicotinic acetylcho-
line receptor, because of the ease of its purification from the
electroplax of fish, was the first to be isolated and described
in detail. Elucidation of the molecular biology of this receptor
allowed the investigation of the other receptors of the class
(Fig. 3.7). They all have ion channels formed from three to
five subunits giving rise to pentamer, tetramer and trimer

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Companion to Psychiatric Studies

domains. The receptor binds to the specific sequence of DNA, are more numerous in the brainstem and spinal cord. Postsyn-
called the enhancer, which in turn enhances transcription by aptic inhibition is mediated by the opening of ion channels
allowing the binding of other transcription factors to the pro- in the postsynaptic membrane which are selectively perme-
moter region. Steroids regulate important brain functions, such able to Cl– and small monovalent cations. Electrophysiological
as reproductive and feeding behaviour, development, cognition studies show that glycine and GABA receptors have similar
and memory, neurogenesis and neuroprotection. Different properties but distinct pharmacology.
roles of steroid receptor activation in psychiatry will be men-
tioned particularly in the section dealing with neuropeptides. Glycine receptors

Steroid and thyroid hormone-like receptors can also be Pharmacological and molecular biological studies of receptors
located on the cell membrane and mediate effects particularly for GABA and glycine have established that several receptor
on neuron excitability that can be detected within minutes macromolecules are involved. The postsynaptic glycine recep-
instead of hours. The responses of these membrane surface tor (GlyR) is a member of the ligand-gated ion channel super-
receptors can be blocked by receptor antagonists and are not sus- family of receptors. Like other ligand-gated ion channels, GlyR
ceptible to blockade of protein synthesis (Fu & Simoncini 2008; is composed of a core made up of four subunits, two of which
Malcher-Lopes et al 2006; Malcher-Lopes et al 2008; Olijslagers are the same. Although these receptors were among the
et al 2008) (see section ‘Peptide regulatory factors’ below). earliest inhibitory mechanisms discovered and are widely
distributed in the CNS, beyond antagonism by strychnine,
Tyrosine-kinase-linked receptors the neuropharmacology of glycine remains poorly understood.
Strychnine (a potent neurotoxic convulsant) is believed to
Growth factors are proteins that stimulate cellular proliferation have its own specific binding site on GlyR close to the integral
and promote cell survival. These proteins are synthesised by ion channel. The amino acids taurine and b-alanine are effec-
different cell types, including neurons and glial cells, and bind tive agonists at GlyR, but alanine, proline and serine are less
to membrane receptors. The most common growth factors that effective. In some synapses GABA and glycine are co-released;
act in the CNS are the neurotrophins (i.e. nerve growth factor, GABA appears to be a weak partial agonist of glycine receptors
brain-derived neurotrophic factor, neurotrophin 3 and neuro- (Shim et al. 2008).
trophin 4/5). Receptors for many growth factors are protein
kinases whose enzymatic activity is stimulated by the specific GABA receptors
ligand, thereby initiating intracellular signalling pathways. The
receptors are relatively specific to their neurotrophin agonist GABA is the main cortical inhibitory neurotransmitter. Its
and have been imaginatively named Trk (for tyrosine kinase) inhibitory actions are Cl– dependent and are blocked by the
A, B and C. TrkA binds nerve growth factor, TrkB binds to plant alkaloid bicuculline. Some effects of GABA are, how-
brain-derived neurotrophic factor and neurotrophin 4/5. TrkC ever, insensitive to bicuculline, indicating the existence of
preferentially binds to neurotrophin 3. The principal signalling two different types of GABA receptors. The classical GABAA
pathway involves the activation of phosphotidylinositol 3- receptor is a ligand-gated ion channel that has an integral trans-
kinase (PI3K), production of phosphatidylinositol triphosphate membrane Cl– channel that mediates inhibitory transmission
and activation of the serine/threonine kinase Akt. Akt stimu- by opening and allowing Cl– entry. GABAB receptors are cou-
lates second messengers that activate the synthesis of various pled to G proteins and linked to Ca2þ or Kþ channels. GABAC
proteins with cell protectant functions. Another consequence are located in the retina.
of Trk-receptor activation is the stimulation of MAP kinases
or extracellular signal regulated kinases (ERKs). ERK activity GABAA and GABAB receptors share inhibitory functions in
is involved in neuritic growth and morphological changes. the CNS and like many other neurotransmitter receptors are
members of both of the major superfamilies with different
These receptors play important roles in development, cell locations in the brain. Figure 3.8 illustrates the probable ionic
survival and growth and hence in synaptic plasticity. It has mechanisms that follow receptor activation for these receptors
been reported that SSRI antidepressants like fluvoxamine, (see also Fig. 11.6). The GABAB receptor, present presynapti-
and TCAs like amitriptyline, increase Trk-related activity. cally, may be more important in the regulation of Ca2þ entry
These and other findings suggest a role for these receptors in and has been shown to have a role in the modulation of
the regulation and therapeutic actions of antidepressant drugs Ca2þ-dependent neurotransmitter release. GABAA receptors
(Rantamaki & Castren 2008). are more widely distributed than GABAB receptors and appear
to be mainly postsynaptic in location. They are clinically
Amino acid neurotransmission relevant drug targets for anti-convulsants, anxiolytic and
sedative-hypnotic agents.

Inhibitory amino acid neurotransmission GABAA receptors
(IAA)
These receptors are present on most brain neurons, exist in
GABA and the amino acid glycine are the major inhibitory several forms, and have at least four different sites at which
neurotransmitters. GABA receptors are more abundant at ligands may bind. Each of these sites may be occupied simulta-
inhibitory synapses in the brain, whereas glycine receptors neously by their respective ligands, implying that each is a
physically distinct part of the same receptor molecule. A group

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Neuropharmacology CHAPTER 3

GABAA GABA BDZ the d subunit and changes in neuronal excitability and anxiety
Cl– Cl– associated with changes in the ovarian cycle could be related to
the changes in expression of the d subunit observed in mice
Receptor – channel (Mody 2008). GABA deficits have also been implicated as
complex underlying anxiety and mood disorders, as well as Huntingdon’s
disease. Further studies of GABAA receptor subunit composi-
GABAB tion will however be necessary to clarify their participation in
GABA Baclofen normal and abnormal brain function.

Gi PLA Gi Ca2+ GABAB receptors
GDP 2 GDP K+
Gi These are pharmacologically differentiated from GABAA
GDP receptors. They are unaffected by bicuculline and are not sti-
mulated by GABAergic drugs, such as isoguvacine. GABA
Go PLA Go Go binds at both GABAA and GABAB receptors but only GABAB
2 GDP K+ GTP receptors are selectively stimulated by (–)-baclofen (b-p-
GTP chlorophenyl GABA). There is, however, a paucity of specific
PKC antagonists at GABAB receptors with which to explore its
Phospholipid Arachidonic pharmacology.
acid
The GABAB receptor is not associated with an integral Cl–
Fig. 3.8 GABAA and GABAB receptors. The GABAA receptor channel. Instead, it is coupled to adjacent Ca2þ channels by
complex with its central Cl– ion channel is modulated by G proteins and its structure shows it to be a member of
benzodiazepine binding (BDZ), which may increase Cl– currents the superfamily of receptors characterised by a heterodimer,
composed of two similar but distinct subunits: GABAB1 and
(shown by a thicker arrow). GABAB receptors are coupled to two GABAB2. Each subunit has a specific role, with agonists inter-
G proteins affecting Kþ (Gi) and Ca2þ (Go) permeabilities in opposite acting with GABAB1 and GABAB2 being responsible for
G-protein activation (Pin et al 2007). Binding between GABA
directions. or the agonist baclofen at the GABAB1 receptor selectively
opens Kþ channels and closes Ca2þ channels. The GABAB2
of molecular biologists, led by Eric Barnard, achieved the first receptor activates two membrane-bound G proteins. There
purification, then sequencing of the GABAA receptor protein are thus two likely routes along which the GABAB receptor
(Sigel et al 1982). As is also described in Chapter 11, there can modify Kþ and Ca2þ: one involves Gi protein and the
are 19 genes for GABAA receptors, which include 16 subunits other involves Go. Gi inhibits adenyl cyclase, which opens
(a1-6, b1-3, g1-3, d, e, y and p). Three r subunits contribute Kþ channels, while the activation of Go results in the closing
to the GABAC receptor. The major benzodiazepine binding of the Ca2þ channels.
site lies at the a/g subunit interface (Olsen & Sieghart
2008). The most prevalent combination of GABAA receptor Excitatory amino acid neurotransmitters
subunits in the mammalian brain is two a1 subunits, two
b2 subunits and one g2 subunit. Differences in GABAA recep- Excitatory amino acid neurotransmitters (EAAs) are the focus
tor composition display different properties – e.g. receptors of considerable current research, with extensive evidence
with a1, 2, 3 or 5 subunits plus the b and g subunits are that they provide the CNS with many functions essential
benzodiazepine-sensitive, whereas those composed of the a4 for learning and memory, structural and functional organisa-
or a6 subunits plus the b and g subunits form a specialised tion (plasticity) that occurs in neural development, and neuro-
family of extrasynaptic receptors insensitive to benzodiazepines degeneration. The most abundant EAAs are glutamate and
which mediate tonic inhibition (Jacob et al 2008). aspartate, also the most frequently encountered excitatory
neurotransmitters in the brain.
GABAA receptor trafficking and subunit expression have
been implicated in the development of epilepsy, with multiple Glutamate activates both ligand-gated ion channels (called
distinct mutations in the a, g2 and d subunits identified. ionotropic glutamate receptors (iGluRs)) and G-protein-
Changes in subunit expression have also been associated with coupled receptors (called metabotropic glutamate receptors
the tolerance, dependence and withdrawal symptoms that (mGlu)). iGluRs are divided into three different types accord-
can develop following chronic use of alcohol or benzodiaze- ing to the agonist response: N-methyl-D-aspartate (NMDA),
pines (Goodman 2008). Altered neurotransmission involving a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)
GABAergic synapses in the frontal cortex has been postulated and kainic acid (KA) receptors. Currently there are eight sub-
to contribute to the cognitive deficits associated with schizo- types of mGlu identified which have been subdivided into three
phrenia, which could be related to altered expression of recep- groups according to their sequence homology and response to
tor subunits. For instance, mice with an a3 knockout subunit agonists.
in the GABAA receptor exhibit attenuation of prepulse inhi-
bition of the acoustic startle reflex (a common finding in AMPA receptors are widely distributed but are highly
schizophrenia) which was normalised by treatment with the concentrated in the cerebellum. Elsewhere, their density is
antipsychotic D2-receptor antagonist haloperidol (Yee et al
2005). Neurosteroids modulate GABAA receptor function at

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Companion to Psychiatric Studies

markedly different from that of NMDA receptors. AMPA chronically, causes neuronal degeneration by excessive excit-
receptors are the synaptic effectors at most glutamatergic atory neuronal stimulation. This model of excitatory neurotox-
junctions, where they act to depolarise the postsynaptic mem- icity by exogenous compounds (as in lathyrism) or endogenous
brane by opening non-specific cation-carrying channels. In nor- compounds (as proposed for Huntington’s disease) has
mal (i.e. physiological) situations, the NMDA receptor channel been extended to include other neurodegenerative disorders,
is blocked by the binding of an Mg2þ ion, so it seems likely including Alzheimer’s disease, head trauma, brain ischaemia
that it is silent. Thus, the normal signalling function of gluta- and epilepsy (Olney 1989). During situations in which the
mate must take place via the other receptor types. In cells brain is deprived of oxygen (e.g. difficult birth, heart attack,
with both AMPA and NMDA receptors, the depolarisation stroke, choking, drowning, strangulation, smoke inhalation)
due to AMPA receptor activation may reach levels where the ATP production and energy-dependent processes are halted
Mg2þ is released from the NMDA receptor and its activation within a few seconds, ion gradients across the membrane
follows. The consequent influx of Ca2þ ions leads to the intra- disappear, and glutamate transporters, driven by sodium
cellular cascade described above, whose final action may be gradients, reverse and let glutamate into the extracellular
either to change the sensitivity of the cell to excitatory trans- space. Excessive stimulation of glutamate receptors leads to
mission for a very long time (long-term potentiation or LTP) sodium and calcium entrance with subsequent oxidative
or, in less physiological conditions, to promote cell death. damage, oedema and lysis of the cell – i.e. excitotoxicity.
Anti-excitotoxic agents have been difficult to produce because
Because of this potential for ‘good’ or ‘evil’, the NMDA a generalised inhibition of glutamate receptors, even for a
receptors have been the subject of extensive study. They are short while, would have unwanted side-effects. The NMDA
made from at least one NR1 subunit and a selection from antagonist, memantine, is however licensed for the treatment
NR2A–D. The time-course of action is determined by which of moderate to severe Alzheimer’s disease, dementia and
of the NR2 subunits contribute to the receptor confirmation. neuropathic pain (Chen & Lipton 2006; Ginsberg 2008).
Receptors with NR2D subunits (common during development
but less common in the adult) have a half-time for closing of Kainate (KA) receptors, of which five subtypes have been
many seconds whereas the NR2A subunits confer a much more identified by molecular cloning, also mediate excitatory neuro-
conventional time-scale in the tens of milliseconds. transmission. In situ hybridisation and immunohistochemical
studies locate KA receptors throughout the nervous system,
It has also been shown that NMDA receptors are linked in pre-and postsynaptically. Systemic or local treatment with
the postsynaptic membrane to a very large (>600) group of KA induces convulsions and neurotoxicity and has been used
cytoskeletal and signalling molecules whose functional signifi- as an animal model for temporal lobe epilepsy (Vincent &
cance is still to be fully explored but which may allow differ- Mulle 2009), while kainite antagonists have potential as anti-
ent routes of intracellular signalling downstream from the convulsants and neuroprotectants. The lack of selective
receptors in different circumstances (Husi et al 2000). agonists and antagonists for KA receptors has delayed under-
standing of their actions, though pharmacological agents are
NMDA receptors include a binding site for glycine and also now available (Bunch & Krogsgaard-Larsen 2008). GluK1
for phencyclidine (PCP). Interactions between these receptor antagonists have, for example, been shown to be effective in
sites and the ion channels they regulate may prove as complex animal models of epilepsy, neurodegeneration and migrane
as the GABA–benzodiazepine ion channel. Although initially (Jane et al 2009).
introduced as an anaesthetic, PCP is a potent psychotomi-
metic (‘angel dust’), and its drug-induced psychosis has been Cholinergic neurotransmission
advanced as a useful model of schizophrenia. A similar psy-
chosis can be induced by benzomorphan drugs, which are syn- Acetylcholine is a widely distributed neurotransmitter present
thetic opiates (such as cyclazocine) that activate s opiate in many regions of the brain and spinal cord. It is present
receptors. PCP and s opiate receptor activation antagonises in the neocortex (from the nucleus basalis of Meynert), in
the excitatory effects of NMDA activation but does not affect neostriatal interneurons and the septal–hippocampal pathway,
AMPA receptors. Since many glutamate-releasing nerve term- as well as in all motor neurons. Some central effects of acetyl-
inals also have presynaptic mGLuRs whose activation reduces choline can be mimicked by muscarine and antagonised by
glutamate release, drugs that are agonists at mGLuRs are also atropine (termed ‘muscarinic effects’). Other effects of acetyl-
suggested to be antipsychotic, and have been shown to reduce choline are mimicked by nicotine, not antagonised by atropine
the effects of NMDA activation in animals. It has been but selectively blocked by tubocurarine (‘nicotinic effects’).
proposed that schizophrenia results from NMDA receptor The two types of cholinergic effect are mediated through
hypo-function, with the consequent suggestion that boosting two classes of cholinergic receptor: muscarinic and nicotinic.
receptor function may be a pharmacological approach to ther-
apy. As glycine acts as a co-agonist site on the NMDA recep- Nicotinic receptors are ligand-gated ion channels and, when
tor, an inhibitor of glycine transporter-1 protein and glycine activated by ligand binding, produce a rapid increase in cellular
have together been added to antipsychotic drugs with some permeability to Naþ and Kþ, thereby increasing neuron activ-
benefit, particularly on negative symptoms (Shim et al 2008). ity and neurotransmitter release. Muscarinic receptors on
the other hand are G-protein-coupled and are not necessarily
Glutamate and its analogues are potent neurotoxins and only linked to ion channels. The structures of nicotinic and
exogenous NMDA agonists are established neurotoxins. Kainic muscarinic receptors show that they belong to two distinct
acid is found in red marine algae digenia simplex (called, in
Japanese, kaininso), while the legume Lathyrus satirus con-
tains b-N-oxalylamino-L-alanine (BOAA) which, if ingested

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Neuropharmacology CHAPTER 3

superfamilies of receptor types. The channel of the nicotinic startle reflex. Partial nicotinic agonists for the treatment of
cholinergic receptor is composed of five homologous subunits. schizophrenia are under development, while a partial nicotinic
The neuromuscular nicotinic receptor contains four distinct agonist selective for the a7 receptor (DMXB-A) has been
subunits (a, b, d, g) arranged as a pentamer (the g subunit is reported as efficacious, though again mainly on the negative
replaced by an E subunit in adult muscle). Nicotinic receptors symptom domain (Freedman et al 2008). Other efforts are
in the CNS are also pentamers but comprise only two subunits centred round exploring the therapeutics for pain relief and
(a and b). Brain nicotinic receptors are open to complex varia- Alzheimer’s disease.
tion, as there are multiple forms of both a and b subunits, and
it appears that different parts of the brain contain different Drugs affecting muscarinic receptors
combinations of a and b subtypes (Gotti et al 2007). Twelve
genes coding for the nicotinic receptor subunits have so far The development of muscarinic receptor agonists has been
been cloned and, like all of the other members of the ligand- the target for potential treatments for cognitive disorders, in
gated ion channel superfamily, they encode for peptides particular Alzheimer’s disease. For instance, the M1 musca-
that all have a relatively hydrophilic extracellular N-terminal rinic receptor is the predominant subtype expressed in cortex
portion, followed by three hydrophobic transmembrane and hippocampal areas, with recent studies suggesting that
domains, a large intracellular loop, and then a fourth hydro- M1 receptor-activated signalling pathways may inhibit the
phobic transmembrane domain. deposition of b amyloid peptide, a key pathological feature of
Alzheimer’s disease (Eglen 2005). Recently, several M1 musca-
Muscarinic cholinergic receptors also exist as various rinic agonists (i.e. alvameline, milameline, sabcomeline, SDZ
subtypes. Molecular-cloning studies have revealed five mole- 210-086 and xanomeline) have been tested clinically, though
cularly distinct mammalian muscarinic receptor subtypes, in spite of important cognitive enhancing effects, most trials
M1–M5. The receptors selectively couple to G proteins and have been discontinued due to considerable side-effects.
their effects are determined by the type of G protein they Xanomeline, however, does appear to improve cognitive and
preferentially activate. The M1, M4 and M5 receptors are pre- psychotic-type symptoms in patients with schizophrenia
dominantly expressed in the CNS, whereas the M2 and M3 (Andersen et al 2003; Shekhar et al 2008).
receptor subtypes are widely distributed both in the CNS
and in peripheral tissues. Anticholinergic drugs in parkinsonism

Drugs affecting cholinergic Until the introduction of L-dopa and decarboxylase inhibitors,
neurotransmission anticholinergic drugs formed the mainstay of treatment
for parkinsonism and still occasionally find a place. They are
Drugs affecting acetylcholine synthesis however especially useful in drug-induced parkinsonism
(Chapter 11). The anticholinergic drugs used to treat drug-
Acetylcholine is synthesised in a single step from acetyl coen- induced parkinsonism are tertiary amines (benztropine, trihexy-
zyme A (produced in neuronal mitochondria) and choline phenidyl and procyclidine). Their extra-CNS antimuscarinic
(from the liver), which is catalysed by choline acetyltransfer- effects are much weaker than those of atropine. Diphenhydra-
ase. Synthesis of acetylcholine can be increased by choline mine is an antihistamine drug that has slight anticholinergic
administration because the synthetic enzyme is not fully properties and is especially well tolerated by old people.
saturated. Cholinergic receptors have important roles in facili-
tating cognitive functions and acetylcholinesterase inhibitors, Anticholinesterases
which increase ACh levels in the brain, are targets for the
pharmacotherapy of Alzheimer’s disease. Anticholinesterase drugs inhibit the enzyme acetylcholinester-
ase and cause acetylcholine to accumulate at cholinergic
Drugs affecting acetylcholine release synapses, the prototype drug being physostigmine. Others
were developed as insecticides and investigated for use in
Newly synthesised acetylcholine is preferentially released on chemical warfare. These latter types cause irreversible inhibi-
stimulation from storage in presynaptic cholinergic terminals. tion of acetylcholinesterase. The mechanism of action of anti-
Black widow spider venom produces a rapid release of acetyl- cholinesterases (including physostigmine) is based on their
choline and also causes morphological changes in the presynap- binding with the enzyme and, in the case of physostigmine
tic storage vesicles. and neostigmine, hydrolysing slowly. The terms ‘reversible’
and ‘irreversible’ as applied to anticholinesterases are only
Drugs affecting nicotinic receptors relative and refer to the speed at which the enzyme recovers
function. In psychiatry, the main use of physostigmine is
The first thing that comes to mind when nicotine is mentioned experimental in Alzheimer’s disease, where it may transiently
is tobacco, addiction and smoking cessation. Efforts to produce produce a modest improvement in mental functions. Rarely,
drugs to aid in this addiction (e.g. gum, spray, patches) tar- intravenous physostigmine may be used to reverse a psychosis
get nicotinic receptors. Varenicline for smoking cessation is induced by antimuscarinic drugs but physostigmine does
among the recent drugs targeting neuronal nicotinic receptors. not reverse the anticholinergic cardiotoxic effects of tricyclic
Excessive smoking in schizophrenics has been proposed as a antidepressants. In recent years, acetylcholinesterase inhibi-
form of self-medication and nicotine can decrease the acoustic tion has reached clinical fruition with the introduction of
donepezil, rivastigmine and galantamine (cf. Chapter 11).

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Companion to Psychiatric Studies

Noradrenergic neurotransmission Drugs affecting the storage of NA

Adrenoceptors Most NA is stored in a presynaptic complex of NA, adenosine
triphosphate (ATP), metallic ions of magnesium, calcium
An understanding of the classification and properties of the and copper, and proteins called chromogranins. Dopamine
different types of adrenoceptor is essential to understanding b-hydroxylase is present in NA storage vesicles, probably in
the diverse effects of catecholamines and the neuropharma- association with the vesicular limiting membrane. NA is taken
cology of this system. Physiological studies by Ahlquist in up into storage by an active transport mechanism that is
1948 suggested two types of adrenoceptor, termed a and b, magnesium-dependent and requires ATP, although a little
an initial distinction subsequently supported by observations NA is available in the cytoplasm. The Rawalfia alkaloids (e.g.
on adrenergic antagonists at a adrenoceptors (e.g. phenoxyben- reserpine and tetrabenazine) disrupt NA storage and inhibit
zamine) and b adrenoceptors (e.g. propranolol). Pharmacolog- NA uptake into storage vesicles – reserpine causes irreversible
ical and molecular cloning approaches have distinguished nine damage to granules, whereas tetrabenazine has reversible
adrenergic receptors subclassified into three major families effects. These processes can be relatively slow, so that NA
(a1, a2 and b). a1adrenergic receptors are important in smooth released from storage may be degraded by intracellular mono-
muscle contraction and a2 in decreasing pancreatic insulin amine oxidase before it can bind with postsynaptic receptors.
secretion. a adrenoceptors are present in the iris, where they Reserpine can initially produce postsynaptic adrenoceptor
stimulate contraction of the radial muscle, thus producing stimulation by releasing NA, and in the presence of mono-
dilatation. They are also present in the eyelid where their amine oxidases it releases the relatively large storage pool onto
stimulation raises the lid. The heart contains b1 receptors, the postsynaptic receptors.
which mediate increases in both the rate and force of cardiac
contractions. All adrenergic receptors are members of the Drugs affecting the release of NA
G-protein-coupled receptor superfamily.
NA is released along with the contents of the storage vesicles
Drugs affecting noradrenergic by a calcium-dependent process involving fusion of the vesicles
neurotransmission with the presynaptic membrane and also involving prostaglan-
dins (PGE2 inhibiting, and PGE2a facilitating release). Release
Some drugs act specifically at noradrenergic (NA) synapses, may be regulated by prostaglandins and other local hormones
whereas others affect several monoamines. Tricyclic antide- acting on NA nerve terminals. Presynaptic catecholamine
pressants are believed to have mood-elevating actions because receptors (autoreceptors) are important in the regulation of
of their inhibition of uptake of monoamines, particularly NA impulse-induced NA release, but presynaptic receptors may
and serotonin, from the synaptic cleft. These actions of anti- be sensitive not only to the local concentration of NA but also
depressants have led to the ‘monoamine hypothesis of affec- to acetylcholine, cAMP, prostaglandins and neuropeptides, like
tive disorders’. Simply stated, the hypothesis postulates that thyrotrophin-releasing hormone.
in depressive illness there is reduced efficiency of neuro-
transmission at NA and/or serotonergic synapses and that this Drugs that release NA quickly enough to bind with postsyn-
may involve abnormalities in the affinity of monoaminergic aptic receptors are called ‘indirectly acting sympathomimetic
receptors for their endogenous ligands (cf. Chapter 11). amines’. Examples are amphetamine, tyramine and ephedrine.
Some drugs inhibit NA release from storage, for example anti-
Drugs inhibiting NA synthesis hypertensive agents such as debrisoquine, bethanidine and gua-
nethidine. These drugs do not readily cross the blood–brain
NA is synthesised from L-tyrosine in three steps: L-tyrosine is barrier (their lipid solubility is low), and they therefore have
hydroxylated to L-dopa (by tyrosine hydroxylase), L-dopa is few psychotoxic effects.
decarboxylated to dopamine (by aromatic-L-amino-acid decar-
boxylase) and dopamine is then hydroxylated to NA (by dopa- NA serves multiple brain functions including control
mine b-hydroxylase). Tyrosine hydroxylase is inhibited by of attention, learning and memory and emotional responses
a-methyl-p-tyrosine, a drug used experimentally to prevent during stress. Preclinical models of addiction have implicated
the synthesis of dopamine, NA and adrenaline. Carbidopa inhi- NA in sensitisation and drug-seeking behaviours. In clinical
bits aromatic-L-amino-acid decarboxylase at sites outside the studies, adrenergic blockers have shown promise as treatments
CNS and can be given at the same time as L-dopa, when it will for cocaine abuse and dependence, especially in patients
prevent enhancement of dopamine synthesis outside the CNS. experiencing severe withdrawal symptoms. For instance,
Dopamine b-hydroxylase is inhibited by disulfiram and by blockade of NA synthesis (disulfiram) prolongs the drug-free
FLA63. Synthesis of NA can also be disrupted by the structur- intervals and the NA a2-agonist, lofexidine, reduces the crav-
ally similar precursor, a-methyldopa. This is synthesised to ing (Sofuoglu & Sewell 2008). Bupropion is a noradrenaline
a-methylnoradrenaline, which then acts as a ‘false neurotrans- and dopamine reuptake inhibitor used mainly as an antidepres-
mitter’ - that is, it is released by the usual mechanisms sant. However, its action as a nicotinic antagonist has been
involved in NA release but it is much less effective at NA exploited as a smoking cessation aid.
receptors.
Drugs acting on adrenergic receptors

All adrenergic receptors subtypes have a widespread distribu-
tion in the brain although their function is poorly understood.

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Neuropharmacology CHAPTER 3

Future studies using genetic techniques will be able to over- than the better-known a adrenoceptor antagonist, phentol-
come the problem of finding specific agonists and antagonists amine. Chronic administration of tricyclic antidepressants,
for these receptors that can cross the blood–brain barrier. but not short-term treatment, reduces noradrenaline-coupled
adenylate cyclase activity and also reduces the number of
Alpha adrenoceptor agonists include NA and adrenaline. b receptors in brain tissue. These effects do not seem to be
NA acts mostly through a adrenoceptors and adrenaline largely limited to one type of antidepressant treatment but are found
through b adrenoceptors. Phenylephrine and clonidine are with tricyclic drugs, mianserin, iprindole, monoamine oxidase
directly acting a adrenoceptor agonists with few b adrenocep- inhibitors and also in an animal model of electroconvulsive
tor effects, and their actions are therefore similar to those of therapy. Some tricyclic antidepressants may therefore act
NA. Isoprenaline is a synthetic catecholamine acting only on by initially increasing the synaptic concentration of NA,
b receptors, where it is more potent than either adrenaline which in turn reduces the sensitivity and/or number of
or NA. Salbutamol, a selective b2 adrenoceptor agonist, has b adrenoceptors. The initial increase of NA may be caused
been used as an antidepressant, the rationale deriving from by inhibition of NA uptake, blockade of presynaptic inhibitory
the ‘amine hypothesis of depression’ (above) where a postu- autoreceptors or actions at other sites.
lated reduction in the functional efficiency of neurotransmis-
sion at mood-regulatory monoamine synapses is accompanied Drugs affecting NA uptake
by increased postsynaptic sensitivity to those monoamines.
Administration of a selective monoaminergic receptor antago- Antidepressants and euphoriants such as cocaine and amphet-
nist, such as salbutamol, might therefore allow re-establishment amine act rapidly on the presynaptic reuptake of NA. The struc-
of more efficient neurotransmission. Although of theoretical ture of the NA transporter is known and has much in common
interest, this has not evolved into a practical clinical strategy. with other members of the superfamily of neurotransmitter
Alpha adrenoceptor antagonists are used mostly in experimen- transporters. Distribution of the transporter matches the locali-
tal work, though phentolamine (a reversible a adrenoceptor sation of NA neurons in the CNS (Pacholczyk et al 1991). The
antagonist) is useful in the emergency treatment of hyper- transporter may be important in neurodegenerative diseases.
tension and the diagnosis of phaeochromocytomas. Potent neurotoxins, such as l-methyl-4-phenylpyridinium
(MPPþ) and 6-hydroxydopamine (6-OH-DA), can be actively
NA is critical in the fast response to stress and it seems to taken up by the NA transporter and, if allowed to accumulate
remain hyper-reactive in chronic states like post-traumatic in neurons, cause selective neuronal death. The transporter is
stress disorder. To decrease the centrally hyperactive NA an important site of action of mood-affecting drugs and its
state, NA receptor blockers (prazosin or propranolol) or the further study (e.g. binding to novel, potentially antidepressant
a-agonist (clonidine) have been administered with some compounds) may facilitate new drug development. It may also
degree of success. Clonidine acts at the presynaptic level to prove relevant to understanding the genetic contribution to
decrease the release of NA. Some positive results have also affective disorders.
been observed after clonidine administration in the treatment
of impulsive behaviour, like gambling (Pallanti et al in press) Uptake of NA from the synaptic cleft is an energy-consum-
as well as in controlling hyperactivity in some cases of atten- ing process that is sodium-dependent and involves ATP. Some
tion deficit hyperactivity disorder and in Gilles de la Tourette drugs inhibit the uptake of monoamines from the synaptic
syndrome, by reducing tics, improving hyperactivity and cleft, thought to be the principal action of tricyclic antidepres-
decreasing obsessive–compulsive symptoms (Palumbo et al sants. These drugs affect both NA and serotonin uptake (cf.
2008; Srour et al 2008). Chapter 11) but have little effect on dopamine. The tertiary
amines imipramine and amitriptyline, in contrast, mostly
Some b adrenoceptor antagonists may have local anaes- affect the uptake of serotonin. Secondary amines like desipra-
thetic-like activity on membrane fluidity as well as actions at mine and nortriptyline largely affect NA. Many tertiary amines
adrenoceptors. These drugs are used mostly in the control of are metabolised to secondary amines, so in reality the tertiary
hypertension, where their exact mode of action is unknown, amines often affect both NA and serotonin uptake. A number
and the relief of angina. Non-selective b adrenoceptor antago- of drugs have been developed to act selectively on serotonin or
nists include propranolol and atenolol. Atenolol and metopro- NA uptake but there are no clear differences in antidepressant
lol are non-selective b1 adrenoceptor antagonists that in large activity between the two. Inhibition of uptake is evident from
doses affect all b receptors, acting at both pre- and postsynap- pharmacological studies within 24 hours of administration of
tic sites. Presynaptic b1 receptors facilitate noradrenaline the drug but clinical effects are not typically seen for about
release, whereas presynaptic b2 receptors are inhibitory. These 10–20 days. Because tricyclic drugs and related compounds
receptors may be involved in the pathogenesis of affective were derived from the phenothiazines, they share several phar-
symptoms and effective antidepressants could exert some or macological properties with them. In particular, they have
all of their effects at these sites (cf. Chapter 11). anticholinergic and antihistaminergic effects. The anticholiner-
gic effects are evident within hours of first administering the
Antidepressants and adrenergic receptors drug, and tolerance usually develops before the onset of the
antidepressant effect. For these reasons, the anticholinergic
There is a close relationship between the potencies of tricyclic effects of the tricyclic antidepressants are probably not rele-
antidepressants to occupy postsynaptic a1 adrenoceptors and vant to their antidepressant action. Further, the incidence of
their sedative–hypotensive effects. The tertiary amines (e.g. anticholinergic side-effects does not differ between patients
amitriptyline) are more potent at these sites than secondary
amines (e.g. nortriptyline) and are only slightly less potent

63

Companion to Psychiatric Studies

who respond and those who do not respond to a tricyclic. The glial cells to stimulate surviving supersensitive DA receptors.
antihistaminergic effects of tricyclic drugs may prove relevant Alternatively nerve terminals in the basal ganglia contain a
to their antidepressant actions. closely related decarboxylase which could also supply DA
from applied L-dopa.
Selective NA uptake inhibitors (reboxetine, desipramine)
have been particularly recommended in depression charac- Dopamine storage
terised by lack of motivation, desire to sleep during the day,
fatigue and decreased cognitive functions, symptoms possibly DA is stored in presynaptic complexes of DA, ATP, magne-
associated with impaired NA function, though this remains sium, calcium, copper and chromogranins. Drugs that dis-
to be validated. rupt the storage of noradrenaline, like Rawolfia alkaloids and
tetrabenazine, also disrupt DA storage complexes, and many
Drugs affecting degradation of NA of the behavioural sequelae of their administration may be
related to the action on DA storage rather than on that of
NA that is not taken up by the presynaptic terminal from the noradrenaline.
synaptic cleft can diffuse into the postsynaptic membrane,
where it is degraded by the enzymes monoamine oxidase and Dopamine release
catechol-O-methyl-transferase (COMT). Monoamine oxidases
are a group of enzymes that are present in a wide variety of tis- DA is released from central dopaminergic terminals by two
sues, where their substrate specificity and physical properties discrete mechanisms that differ in their sensitivity to DA
may differ (see Chapter 11). While the antidepressant actions uptake inhibitors. An energy-dependent transport mechanism
of monoamine oxidase inhibitors (MAOIs) such as tranylcy- for DA uptake is inhibited by nomifensine, benztropine and
promine, pargyline, phenelzine and clorgyline (selective type cocaine. A second carrier-independent mechanism for DA
A inhibitors) are produced largely by their inhibition of mono- release is dependent upon extracellular Ca2þ concentrations
amine oxidase, they also affect aromatic-L-amino-acid decar- and involves fusion of DA-containing vesicles with the presyn-
boxylase and various other oxidases and inhibit uptake of NA aptic membrane upon the Ca2þ influx that follows action
and serotonin, though the clinical relevance of these effects potentials. This type of release is facilitated by amphetamine
is not known. The metabolism of concomitantly administered at concentrations much lower than those required for amphet-
drugs may also be affected by monoamine oxidase inhibitors, amine to stimulate postsynaptic catecholaminergic receptors.
so that the action of barbiturates may be prolonged and the Amphetamines stimulate rapid release of DA, inhibit its
effect of amphetamine exaggerated. uptake from the synaptic cleft and also inhibit its degradative
enzyme, monoamine oxidase.
Monoamine oxidase inhibitors also reduce the ‘first-pass’
pre-systemic degradation of tyramine after its intestinal The dopamine hypothesis of schizophrenia
absorption. Tyramine, a naturally occurring amino acid present
in many foods, is selectively taken up into adrenergic neurons The ‘dopamine hypothesis of schizophrenia’, simply stated,
(by a high-affinity system), where it releases stored NA. postulates that certain dopaminergic pathways are overactive
Monoamine oxidase inhibitors thus potentiate the effects of in schizophrenia and so cause the symptoms of an acute
tyramine and other indirectly acting sympathomimetic agents. schizophrenic episode. Clinical studies indicate that drugs
like L-dopa or amphetamine, which potentiate dopaminergic
Dopaminergic neurotransmission activity, may induce or exacerbate schizophrenic symptoms.

The modern era of pharmacotherapy in psychiatry began with When the antipsychotic drugs were first introduced, their
the introduction of phenothiazine antipsychotics in 1952 and mode of action was unknown. At first, studies in the periph-
was quickly followed by the development of phenothiazine- eral nervous system suggested that the anti-adrenergic effects
derived tricyclic antidepressants. of chlorpromazine probably explained its antipsychotic action,
perhaps by reducing arousal. However, the fact that potent
Dopamine (DA) synthesis, storage anti-adrenergic agents had no antipsychotic benefit did not
and release support this hypothesis. Carlsson & Lindqvist (1963) first
suggested that DA receptor blockade was the basis of anti-
Dopamine synthesis psychotic effects. The low activity of butyrophenone antipsy-
chotics at DA receptor sites linked to adenylate cyclase
DA is synthesised from the hydroxylation of the amino acid stimulation was seen as evidence against this idea. It was
L-tyrosine (by tyrosine hydroxylase) to L-dopa, which is sub- supported, however, by the recognition of two types of DA
sequently decarboxylated (by aromatic-L-amino-acid decar- receptor. One (called D1) was linked to adenylate cyclase
boxylase) to form dopamine. Oral administration of L-dopa stimulation, and another, higher affinity one (called D2) was
increases DA synthesis. In Parkinson’s disease, dopaminergic sometimes associated with adenylate cyclase inhibition and
neurons are damaged and have a much-reduced capacity to exhibited preferential binding of butyrophenones.
synthesise DA. Adjacent glial cells retain DA synthetic capac-
ity and, during L-dopa therapy, DA may leak out from these Neuropharmacological studies provide virtually all the evi-
dence to support the ‘dopamine hypothesis of schizophrenia’.

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Neuropharmacology CHAPTER 3

Although some of the newer so-called ‘atypical’ antipsychotic to have a different pre-synaptic (D2short) and post-synaptic
agents are weak DA receptor antagonists, all effective antipsy- (D2long) localisation (Usiello et al 2000). D2 receptors also
chotics are believed to share the ability to impair dopaminergic modulate intracellular Ca2þ levels by acting on ion channels
neurotransmission. Postmortem studies of schizophrenic brains or by triggering its release from intracellular Ca2þ stores.
have demonstrated increased DA receptor (D2) densities, but Downstream from PKA, the DA and cAMP regulated phos-
these densities are probably considerably influenced by ante- phoprotein, DARPP-32 (i.e. with molecular weight of 32) is
mortem drug treatments. Positron emission tomographic stud- a protein phosphatase inhibitor that plays a role in the integra-
ies of D2 receptor binding in antipsychotic-naive schizophrenic tion of various signals. After phosphorylation at Thr-34,
patients have provided conflicting results. DARPP-32 becomes an inhibitor of protein phosphatase I.
On the other hand, phosphorylation at Thr-75 converts it
The CNS location of the site of antipsychotic drug action into an inhibitor of PKA. In fact, DARPP-32 can be phos-
is unknown and subject to much debate. DA receptors are phorylated in another two residues by at least another two
present in the basal ganglia, the mesolimbic system, the kinases. Through these actions, DARPP-32 has been postu-
tuberoinfundibular region and, to a much lesser extent, in lated as a neuronal integrator of cAMP and calcium signals as
the cerebral cortex. Studies on the effects of dopaminergic well as the sum of kinase and phosphatase activities. Loss of
transmission of psychotomimetic agents such as amphetamine, DARPP-32 in knockout mice reduces their sensitivity to
PCP and benzmorphan point to a possible common mecha- cocaine. DARPP-32 Thr-34 mutant mice show reduced sensi-
nism of psychotic action. Carlsson (1988) proposed that tivity to the rewarding and acute locomotor activating effects
‘information overload’ and ‘hyper-arousal’ are integral features of cocaine. Therefore DARPP-32 seems to play a critical role
of many psychotic illnesses. He postulated that these features in amplifying the actions of D1 receptor/cAMP signalling to
arise because of impairment in the mesolimbic system’s pro- ensure activation of downstream signalling targets.
tective effects on cortical function. In health, Carlsson argued,
mesolimbic glutamate-releasing neurons oppose mesolimbic It has recently been proposed that D2 receptors can func-
dopaminergic pathways and maintain this protective function. tion through a cAMP-independent mechanism via a protein
In this model, mesolimbic DA dysregulation is considered kinase B (Akt)/glycogen synthase kinase 3 (GSK-3) signall-
secondary to frontal dysfunction. A further recent elaboration ing cascade mediated by b-arrestin (Beaulieu et al 2007).
on the DA hypothesis of schizophrenia considers the function In fact, b-arrestin knockout mice display reduced behavioural
of the mesolimbic DA system in assigning importance, or responses to DA receptor agonists, GSK-3 inhibitors reduce
salience, to stimuli or ideas (Kapur 2003; Murray et al locomotor hyperactivity to amphetamine and mice lacking
2008). It is proposed that DA attaches a label (e.g.‘dangerous’, the Akt isoform (Akt1) show enhanced acoustic pre-pulse
‘pleasant’, etc.) to stimuli and ideas and that with the labels in inhibition. While D3 receptors have a high affinity for some
place, motivation and goal-directed behaviour easily follows. so-called ‘atypical’ antipsychotic drugs (and, interestingly, for
In schizophrenia, excess DA leads to the assignment of ‘labels’ DA autoreceptor inhibitors) and D4 have a high affinity for
or salience to irrelevant or insignificant thoughts or events, clozapine, this has not so far translated into anything of clinical
creating a psychotic state. value nor anything new in understanding mode of action.
Furthermore, pharmacological studies have not detected
Dopamine receptors differences between postsynaptic D2 receptors located in the
striatum (where extrapyramidal side-effects arise) and in
Two subtypes of DA receptors were initially identified – D1 the mesolimbic system, where the antipsychotic action is
and D2 type. Subsequently, multiple molecular clones of D1- presumed to be located.
and D2-like receptors have been observed. All DA receptor
subtypes are coupled to G proteins (Gs/olf or Gi/o) and regu- Discovery of DA receptor isoforms suggests a means by
late cAMP-PKA, though there also seems to be a D1–D2 which different dopaminergic neuronal populations might
receptor heterooligomer that is coupled to Gq/11 protein on adjust responses to stimuli (such as chronic exposure to stress
activation of both receptors and stimulates phospholipase C or drugs of addiction). Several alterations have been reported
and intracellular Ca2þ release (Rashid et al 2007). in the D2 and D4 receptor genes when phenotypic information
concerning smoking-related behaviours was analysed for
The family of D1 receptors includes the D1 and D5 subtypes. genetic polymorphisms (Vandenbergh et al 2007). Also, there
They have high affinity for benzazepines and low affinity for are reports of polymorphisms in the human D4 receptor gene
benzamines and are coupled to stimulation of adenylyl cyclase associated with novelty seeking and impulsivity (Munafo et al
activity, leading to increases in cAMP and activation of PKA. 2008).
An important difference between these two receptors subtypes
is the higher DA affinity for D5 compared to D1 receptors. Using various anatomical (e.g. in situ hybridisation and
immunohistochemistry) and genetic techniques (e.g. knockout
D2-like receptors include D2, D3 and D4 receptors. Struc- mice or translating ribosome affinity purification), it has been
tural studies identified two D2 receptor isoforms: the D2 shown that the spiny output cells of the caudate/putamen
receptor isoforms are termed D2short and D2long. The differ- are in two classes. One predominantly expresses D1 receptors,
ence in length is given by 29 amino acids present or absent in makes enkephalin and projects to the globus pallidus and
one of the loops of the receptor. Both versions of receptors thence to the output nuclei of the basal ganglia (substantia
inhibit adenylyl cyclase activity and therefore produce a nigra and the globus pallidus interna), while the other class
decrease in cAMP and activation of PKA. Each receptor seems of spiny neurons makes D2 receptors and substance P and
dynorphin and projects directly to the substantia nigra.

65

Companion to Psychiatric Studies

The balance between these two output pathways is vital for The gene that encodes MAO has been associated with
the normal expression of movement and habit learning and loss aggressive and impulsive behaviours, and can produce a vari-
of DA increases synthetic activity in the enkephalin-containing able number of tandem repeats which results in lower tran-
cells and reduces the activity of the others. Activation of D1 or scriptional efficiency. Humans with these alleles seem to
D2 receptors in spiny output cells mediates function and traf- have impulsive personality traits and Gilles de la Tourette
ficking of glutamate receptors. There is an important cortical patients with this allele are also more impulsive (Lee & Ham
glutamatergic input to caudate/putamen which regulates neu- 2008). MOA inhibitors, like tranylcypromine, reduce the
ronal function at this level. Alterations in dopaminergic signal- degradation of DA by the enzyme. Tranylcypromine also
ling can have important effects on glutamate-mediated plastic reduces uptake of DA but this is probably not relevant to its
changes in the caudate/putamen that impact on cognitive and antidepressant action because drugs such as benztropine
motor function. (a potent DA uptake inhibitor) are not effective antidepres-
sants. In contrast, the actions of the monoamine oxidase B inhib-
Drugs affecting dopaminergic itor, selegeline, seems to be less on the metabolism of amines and
neurotransmission more on the reduction of oxidative stress and its concomitant
neurotoxicity. Clinical trial evidence supports the view that sele-
Drugs affecting dopamine uptake giline delays the need for treatment with L-dopa in Parkinson’s
disease and may slow the rate of disease progression.
Amphetamine and other drugs which release dopamine also
inhibit its uptake and so potentiate the action of DA. Nomi- Drugs affecting dopamine-induced second
fensine and cocaine are also well-established DA uptake inhibi- messenger systems
tors. Benztropine and to a lesser extent benzhexol and
orphenadrine inhibit the uptake of DA and also block cho- Activation of DA receptors leads to changes in intracellular
linergic receptors, actions that contribute to the effects of signalling that ultimately alter gene expression. D1 and D2
these anticholinergic drugs in the treatment of parkinsonism. receptors, through the G-protein-coupled second messenger
As described below large increases in DA release have beha- systems, modify gene expression, such as mClock and mPer1
vioural reinforcing properties that can lead to addiction; devel- genes, or interact with other signalling cascades by mechan-
oping medications to treat stimulant addiction by targeting isms still unclear, resulting in modifications of other signal-
DA uptake transporters has resulted in a very large amount ling systems, such as the extracellular signal-regulated kinase
of compounds such as GBR12909, benztropine, mazindol, (ERK), mitogen-activated protein kinase (MAPK), regulators
methylphenidate and rimcazole that display cocaine-like beha- of G-protein signalling and brain-derived neurotrophic factor,
vioural profiles and could be potential agonist therapy easily quantified following repeated exposure to drugs such
candidates. as cocaine and amphetamine (Imbesi et al 2008; McGinty
et al 2008). Future efforts in drug development will target
Drugs affecting degradation of dopamine such second messenger and molecular transcriptional systems.

Monoamine oxidase (MAO) and catechol-O-methyltransferase Addiction
(COMT) are responsible for degrading the biogenic amine neu-
rotransmitters, including DA. Because of its intracellular loca- Drug addiction has been defined as a chronically relapsing dis-
tion MAO inactivates DA after its uptake into the presynaptic order characterised by compulsive drug use and loss of control
terminal. over drug intake. Addiction as defined comprises three stages:
preoccupation/anticipation, binge/intoxication and withdrawal/
Since there is less DA transporter protein in the prefrontal negative effect (Koob 2008). Administering any drug of abuse
cortex than any other brain regions, prefrontal neurons are (e.g. amphetamine, cocaine, nicotine, alcohol) or engaging in
more dependent on COMT for terminating the action of pleasurable activities (e.g. gambling, eating, sex) is associated
released DA. In humans, a functional polymorphism of the with increased levels of DA, particularly in the nucleus
COMT gene has been identified, a mutation comprising the accumbens and striatum. Activation of D1 receptors is asso-
substitution of valine for methionine. The methionine variant ciated with rewards and promotion of memory traces in the
of the enzyme displays less activity than the valine substitu- form of long-term potentiation. The relative density of D1
tion. Methionine alleles therefore result in reduced COMT and D2 receptors and their sensitivities seem to contribute
enzymatic activity and presumably greater synaptic DA, to the addictive process. Chronic treatment of animals with
whereas the reverse is true for valine alleles, resulting in less drugs of abuse produces genetic alterations that reflect in
synaptic DA and presumably impaired cortical functioning. brain function, which ultimately could lead to abuse and
Inheritance of valine COMT alleles has been associated with addiction (Goodman 2008). A polymorphism located in the
poor cognitive activity and schizophrenia (Meyer-Lindenberg third exon of the D4 receptor gene has been associated with
et al 2005; Diaz-Asper et al 2008). When tolcapone, a non- impulsive personality traits and risk of drug abuse. The A1 allele
stimulant drug which penetrates the blood–brain barrier and of the D2 receptor gene Taql A polymorphism affects D2 recep-
potently inhibits brain COMT activity, is administered to a tor expression and seems to favour addictive behaviours in
group of valine COMT allele expressing subjects, prepulse acous- humans (Stice et al 2008). The design of pharmacological agents
tic inhibition and cognitive performance are increased compared
to a group with the methionine variant (Giakoumaki et al 2008).

66

Neuropharmacology CHAPTER 3

for the treatment of addiction is still under intense investigation Serotonin storage
(Rothman et al 2008). For more detailed reviews, see Goodman
(2008), Koob (2008) and Naqvi & Bechara (2009). Serotonin is transported to the terminals of axons, where
it forms a readily releasable pool. It is stored in presynaptic
Parkinsonism complexes comparable to those storing catecholamines.
The Rauwolfia alkaloids and tetrabenazine reduce serotonin
Restoration of DA neurotransmission is the aim of all effective stores by disrupting these granules. When serotonin storage is
treatments for parkinsonism of any cause. DA-containing cell disturbed, large quantities of serotonin are released, and out-
bodies in the pars compacta of the substantia nigra degenerate side the CNS this causes side-effects such as diarrhoea and
in Parkinson’s disease. In particular, loss of DA results in reduc- abdominal cramps.
tion in the synthesis of striatal substance P in those cells which
make D1 receptors and project directly to the substantia nigra, Serotonin release
and in an increase in the synthesis of enkephalin in the indi-
rectly projecting, D2 receptor-synthesising cells. Current surgi- Serotonin release is a Ca2þ-dependent process, and there is
cal treatment in parkinsonian patients aims to redress the some evidence, as with DA, that release takes place by two
imbalance in the two pathways by surgically reducing the activ- separate mechanisms. The amphetamines and some tricyclic
ity of the indirect pathway with a lesion in the globus pallidus antidepressants release serotonin from storage granules.
interna, or by chronic high-frequency stimulation of the subtha- Amphetamine analogues containing halogen atoms (e.g. fen-
lamic nucleus, which interrupts its normally excitatory actions. fluramine) are more effective in stimulating serotonin release
than those without.
Psychiatric symptoms, particularly depression and anxiety,
are frequently observed in Parkinson’s disease. In the past, Serotonin re-uptake
the clinical symptoms of depression were overlooked or
confused with those of Parkinson’s disease (e.g. flat affect, loss The activity of serotonin is terminated primarily by its uptake
of motivation, fatigue, sleep problems). Administration of into presynaptic terminals. Serotonin binds specific trans-
tricyclic antidepressants, such as desipramine, nortriptyline, porter proteins which exhibit 50% absolute homology with
and imipramine, or selective serotonin uptake inhibitors, the transporters for noradrenaline and DA. The human gene
improves quality of life in these patients (Boggio et al 2005). that encodes the serotonin transporter – SLC6A4 – has been
cloned and is located in chromosome 17q11.2.

Serotonergic neurotransmission Serotonin receptors

Serotonin (5-hydroxytryptamine, 5HT) is present in the The cloning of serotonin receptors has resulted in a new
enterochromaffin granules of the intestines and in blood
platelets. Less than 2% of total body serotonin is in the CNS. nomenclature based on structural and transductional informa-
Early studies of serotonin indicated that disturbances of its
physiology could produce abnormal behaviour, at times strongly tion (Hannon & Hoyer 2008). There are seven families of
suggestive of mental illness. Substances with marked structural
similarities to serotonin possess considerable pharmacological serotonergic receptors currently identified. The 5-HT1 family
potency. Examples are N,N-dimethyltryptamine (DMT) and inhibits adenylyl cyclase and is composed of five subtypes
bufotenine (both present in the cahobe bean). Mexican halluci-
nogenic mushrooms also contain serotonin-related substances, (5HT1A, 5HT1B, 5HT1D, 5ht1e and 5HT1F). They are located
such as psilocybin. All three have a long history of abuse. in limbic areas, such as hippocampus, lateral septum and cin-

Serotonin, like noradrenaline and DA, is localised within spe- gulate cortex, though are also found in raphe nuclei, basal
cific neuronal pathways in the brain, and serotonin-containing
cell bodies are found in discrete brain nuclei, especially the ganglia and cerebellum. The 5HT1C receptor has been reclassi-
midbrain and brainstem raphe nuclei. fied as 5HT2C due to common characteristics with the 5HT2
family. The 5HT2 family couple to protein Gq/11 to increase
Serotonin synthesis, storage and release inositol phosphate and cytosolic Ca2þ, as well as to G12/13
and mediate long-term structural changes in the cell. These
Serotonin synthesis
receptors are present in cortex, claustrum, endopiriform
Serotonin is synthesised from L-tryptophan, being first hydro-
xylated to 5HTP (by tryptophan hydroxylase), which is then nucleus and olfactory areas and in lesser quantities, in basal
decarboxylated to 5HT (by aromatic-L-amino-acid decarboxyl-
ase). The capacity of the brain to synthesise serotonin is ganglia and brainstem. 5HT3 receptors belong to the ligand-
greatly in excess of requirements. Serotonin synthesis can be gated ion channel family and are found in the nucleus of the
increased by oral tryptophan and takes place in neurons, in
both somata and nerve terminals. tractus solitarius, area postrema, hippocampus, amygdala and

cortex. The 5HT4, 5HT6 and 5HT7 receptors couple preferen-
tially to G proteins and promote cAMP formation. 5HT4
receptors are expressed in the olfactory tubercle, islands of

Calleja, substantia nigra, ventral pallidum, striatum, septum,

hippocampus and amygdala, while the 5HT6 type are mainly
found in striatum, nucleus accumbens, olfactory tubercle and

cortex (though moderate expression has also been reported

in other brain areas). The 5HT7 receptor has an extensive
vascular distribution and in addition is expressed in smooth

67

Companion to Psychiatric Studies

muscle and colon. In the brain, it is mainly expressed in the for serotonergic and catecholaminergic reuptake mechanisms.
suprachiasmatic nucleus. Neither function nor preferential The structure of the serotonergic transporter is known
coupling of the 5HT5 receptors have been established, hence (cf. Chapter 11) and has much in common with other
the use of lower case. members of the superfamily of neurotransmitter transporters.
The gene coding for the transporter has also been cloned.
Drugs that are selective partial agonists at the 5HT1A recep- Variants in the human gene that encodes the serotonin trans-
tor include buspirone and ipsapirone, both mild antianxiety porter produce changes in the protein that are now being asso-
agents, while antagonists for 5HT3 receptors have antiemetic ciated with the expression of behaviours varying in severity
efficacy and reduce secretion and motility in the gut and have from mild to, potentially, full psychiatric syndromes. The wide
found a place in the treatment of irritable bowel syndrome. range of serotonin-dependent behavioural abnormalities
Their value in fibromyalgia is under investigation. Thanks to associated with gene variants could have been easily identified
their positive effect on learning and memory, agonists for this by the multiple therapeutic roles of serotonin reuptake
receptor are under development for the treatment of cognitive inhibitors. Variants in the human gene that encodes the seroto-
deficits and Alzheimer’s disease. nin transporter protein are associated with anxiety, obsessive
compulsive disorder, drug dependency, sleep disorders, excess
Chronic treatment with a wide range of antidepressants stress responsiveness and irritable bowel syndrome (Murphy
(including TCAs, MAOIs and atypical antidepressants such et al 2008). The tricyclic antidepressant, clomipramine, was
as mianserin) is known to reduce the number of 5HT1 and the first drug to inhibit serotonergic uptake without also inhi-
5HT2 receptors. Electroconvulsive shocks also decrease biting noradrenergic reuptake, although its metabolite (des-
5HT1A receptors but increase 5HT2 receptor numbers. This methylclomipramine) is a strong inhibitor of noradrenergic
difference may possibly explain why some depressive illnesses reuptake (cf. Chapter 11). Serotonin reuptake inhibitors
do not respond to a therapeutic course of oral antidepressant (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram,
therapy but later respond to ECT. After long-term treatment, escitalopram), all of which are highly potent and selective
antidepressant drugs produce substantial decreases in 5HT2 inhibitors of the serotonin transporter, function at presynap-
receptor numbers, effects that may be greater than their tic terminals. Repeated, long-term administration for 3–6
actions on catecholaminergic systems. For example, amitripty- weeks is required for antidepressant actions and most other
line and imipramine reduce b adrenoceptor binding by about beneficial effects, while treatment for 10–12 weeks
20% but reduce 5HT2 binding by about 40%. MAOIs also or longer is required for efficacy in obsessive–compulsive
reduce serotonin binding site numbers after chronic treatment, disorder. It appears that slowly developing adaptations in
especially selective MAOIs. Abnormalities in serotonin recep- receptor and postreceptor neuronal signalling, responses to
tor function have been put forward as part of the pathophysi- multiple neurotrophins (most notably brain-derived neuro-
ology of depressive illness. Limited support for this hypothesis trophic factor or BDNF), as well as plastic remodelling of
has been found in studies of [3H] serotonin binding to platelets brain regions such as hippocampus, appear to be required
and [3H] serotonin and [3H] spiroperidol binding to cortical for therapeutic efficacy in these conditions (Thakker-Varia
tissue in suicide victims. The hypothesis has been extended & Alder 2009).
to involve increased release of serotonin acting upon hypersen-
sitive postsynaptic serotonin receptors, with this proposed Drugs affecting serotonin degradation
as a possible cause of depressive illness. Cyproheptadine and
methysergide are commonly used serotonergic antagonists. Most serotonin is oxidised by monoamine oxidase to 5-
Structurally, cyproheptadine resembles the phenothiazines hydroxyindoleacetaldehyde and then to 5-hydroxyindoleacetic
and also blocks histaminergic (H1) and cholinergic (M1) recep- acid (5HIAA) by aldehyde dehydrogenase. 5-Hydroxyindole-
tors. Methysergide, structurally similar to LSD, can stimulate acetaldehyde is also reduced by alcohol dehydrogenase to
some serotonergic receptors and, especially in the periphery, 5-hydroxytryptophol. 5HIAA is the major metabolite of 5HT
be an antagonist at others. The physiological and biochemical degradation. Monoamine oxidase inhibitors are the principal
actions of serotonergic receptors appear complex and study drugs to modify serotonin degradation, although it is likely
of their properties has been hindered by lack of specific that serotonin’s synaptic actions are restricted more by the
antagonists or agonists. The recent development of such drugs uptake system than by catabolism.
is certain to add substantially to knowledge of the serotonergic
system and will probably also lead to better understanding of
the mode of action of antidepressants.

Drugs affecting serotonergic Peptidergic neurotransmission
neurotransmission
Many neuropeptides display cognitive-enhancing, antipsy-
Drugs affecting serotonin uptake chotic or antidepressive properties and therefore have become
promising targets for intervention and treatment of numerous
The reuptake systems for serotonin resemble those for the psychiatric illnesses.
catecholamines and are influenced by many antidepressant
drugs. These may differ markedly in their relative affinities

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Neuropharmacology CHAPTER 3

Molecular biology of peptidergic cord areas is accounted for by the long projections of these
transmission cells into those areas. Some widely distributed neuropeptides
(e.g. thyrotropin releasing factor and substance P) are found
Most regulatory substances released by the nervous system in neurons in numerous areas.
are peptides, i.e. amino acids joined by peptide bonds. Unlike
classical neurotransmitters, these compounds are synthesised The coexistence of neuropeptides and ‘classical neurotrans-
as parts of larger molecules that are cleaved by proteolysis mitters’ within the same neuron has been demonstrated at
and carboxylation into active fragments of amino acid chains many sites in the nervous system (Hokfelt et al 1987), the
at the point of release. Local tissue-specific differences in physiological importance of which is unknown. A number of
the activity of processing enzymes can yield important topo- models have however been put forward, some of which may
graphical variations in the proportions of peptide fragments prove to be of relevance to hypotheses concerning changes in
derived from a single precursor. The steps in the biosynthesis receptor sensitivity in psychiatric disorder. In one model, a
of neuropeptides – peptide cleavage, disulfide bond formation, nerve terminal containing serotonin, substance P and TRF
the addition and modification of N-linked and O-linked oligo- responds to low-frequency electrical stimulation by releasing
saccharides, phosphorylation and sulfation – are not unique to serotonin. The released serotonin attaches to the postsynaptic
neuropeptides. Most of the specific steps in the biosynthesis receptors, where it generates a small postsynaptic potential.
of each neuropeptide occur as it travels down the axon in Some serotonin also attaches to the presynaptic serotonergic
large dense-core vesicles. Cleavages in these vesicles occur in receptors (autoreceptors) which inhibit further serotonin
sequential steps. The endoproteolytic cleavage of propeptides release. As electrical stimulation is increased, TRF and sub-
is often the rate-limiting reaction in peptide biosynthesis. Pep- stance P are also released. TRF and serotonin then act synergis-
tidylglycine a-amidating mono-oxygenase is an enzyme found tically on the postsynaptic serotonin receptor to generate an
in large dense core vesicles which acts on the final steps of bio- increased postsynaptic potential, while substance P blocks
synthesis, converting the peptidyl-Gly into the corresponding the serotonergic autoreceptors, preventing inhibition of seroto-
peptide-NH2. Peptidylglycine a-hydroxylating monooxygenase nin release. The three substances thus combine to produce
is another enzyme involved in the a-amidation of the peptide prolonged postsynaptic activation without inducing compensa-
crucial for its biological potency. tory responses at a presynaptic level. These interactions
between a monoamine neurotransmitter and neuropeptides
Neural regulation of neuropeptide may be relevant to long-term changes in homeostatic mechan-
synthesis and release isms, neural learning and long-term potentiation of synaptic
activity. They have also been related to the mode of action
The hypothalamus controls the release of pituitary hormones of antidepressant treatments (including electroconvulsive ther-
in two ways, both of which involve neurons that synthesise apy) and pathological alterations in receptor sensitivity that
and release neuropeptides. In the first, specialised neurons may occur in affective disorders and schizophrenia.
in the hypothalamus synthesise and secrete releasing factors.
In the second, the magnocellular neurons of the hypothalamus Peptidergic receptors
synthesise precursor molecules (preprovasophysin and preproxy-
physin) that are processed and transported to terminals in the Most neuropeptide receptors are seven-transmembrane-G-
posterior pituitary, from which vasopressin, oxytocin and their coupled receptors and are not necessarily confined to the post-
related neurophysins are released. The neuroendocrine neurons synaptic region. It appears that peptides can diffuse a distance
of the hypothalamus are influenced by many types of neuro- from the release site to act on extrasynaptic receptors.
transmitter. Releasing-factor-producing neurons are richly
supplied with noradrenergic, dopaminergic and serotonergic Neuropeptides can function as:
connections.
• neurotransmitters released by one neuron at a presynaptic
Cotransmission of neuropeptides terminal to act on the adjacent postsynaptic membrane;

• neuromodulators that act by modifying the turnover,
release or action of classical neurotransmitters;

• neurohormones released by one neuron to act at a site
distant to the point of release.

Neuropeptides are present in the central nervous system in Neuropeptides in psychopathology
concentrations between 10–12 and 10–15 mol/mg of protein.
Endorphins
These are much lower than the concentrations of the ‘classical
neurotransmitters’, which vary from 10–9 to 10–10 mol/mg of The endorphins (literally, ‘endogenous morphines’) are the
endogenous ligands for the opioid receptors. Their study is a
protein. High concentrations of neuropeptides in the brain rapidly expanding field of research and has given rise to a con-
fusing terminology. The term ‘opiate’ is used to describe drugs
are found in the hypothalamic–pituitary system but some neu- derived from the juice of the poppy Papaver somniferum. The
word ‘opioid’ describes all substances with morphine-like
ropeptides (e.g. cholecystokinin and vasoactive intestinal pep-

tide) have their highest concentrations in the cortex. Others

(e.g. oxytocin and vasopressin) are present in cell bodies only

in the hypothalamus and their presence in other brain or spinal

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Companion to Psychiatric Studies

actions. The word ‘narcotic’ is no longer used in pharmacology, produce tolerance, withdrawal and addiction. Tolerance occurs
although originally it described drugs that induced sleep and when the drug is regularly administered and consists of a
was later applied to morphine-like analgesics. The sites of decrease in response – i.e. larger doses are required to achieve
action of opioid drugs in the nervous system appear to be the the same effect. Proposed mechanisms to account for this
receptors for a number of endogenous ligands, which include phenomenon have included decoupling, internalisation and/or
the pentapeptides, leucine-enkephalin (Leu-enkephalin) and downregulation of receptors or release of anti-opioid neuromo-
methionine-enkephalin (Met-enkephalin). The amino acid dulators. There is extensive cross-tolerance between opioid
sequence of Met-enkephalin is the same as the sequence drugs and when they are administered regularly, tolerance fre-
contained in amino acid residues 61–65 in the pituitary quently develops. This must not however be taken to imply
hormone b-lipotrophin (b-LPH). Other opioid peptides are that withdrawal symptoms will always occur if the drug is
represented in fragments of the b-lipotrophin amino acid removed. The manifestation of withdrawal symptoms demon-
sequence. The C-terminus of amino acid residues 61–91 is strates that an individual has become dependent on the drug.
called b-endorphin. Sequences of amino acid residues 61–76 Symptoms that can follow opioid withdrawal include insom-
are called a-endorphin, while amino acid residues 61–77 are nia, restlessness, anxiety, nausea and vomiting, abdominal
called g-endorphin. The enkephalins and endorphins derived cramps, sweating, piloerection and rhinorrhoea. These symp-
from b-lipotrophin probably belong to separate physiological toms may persist for several days and may be accompanied
systems. b-Endorphin is present in the hypothalamic pituitary by a craving for the drug to be reintroduced. It is important
system, where it is derived from a larger precursor molecule, to note that although withdrawal and dependence can explain
pro-opiomelanocortin (POMC), containing the amino acid the sustained consumption of drugs, they cannot explain
sequences for both b-lipotrophin and adrenocorticotropic hor- addiction.
mone (ACTH). The sources of leu- and met-enkephalins are
not derived from POMC but are produced by cleavage of a sep- An effect common to different kinds of drugs (e.g. alcohol,
arate precursor molecule, ProEnk. The discovery of codeine in nicotine, cocaine, methamphetamine) is activation of CREB
invertebrates generated the search for endogenous morphine. (cAMP response element binding) protein and the result-
Indeed, endogenous morphine has been detected in the rat ing alteration in gene expression related to the development
brain and human plasma. Plasma levels of morphine increase of tolerance and dependence on drugs. Although the CREB-
following surgical procedures and it has been speculated regulated target genes that contribute to these effects are
that it could have an action on the immune system and on the not known, one particular candidate is the dynorphin gene.
development of tolerance to opiates (Stefano et al 2000). Dynorphin is derived from a larger prodynorphin peptide and
contains leu-enkephalin at the N-terminus. Products of this
According to their selectivity, the receptors for endorphins precursor are dynorphin A (1–17) and dynorphin A (1–8), as
are classified as: m, d, k, e and s. There are three subtypes of m well as dynorphin B (1–29). Dynorphins bind to opioid recep-
(m1-3) and two of d (d1-2) according to the different degrees of tors with preference for the KOP opioid receptor. Immuno-
selectivity. The m receptors bind morphine, d receptors enke- histochemically, dynorphin-containing cells are found in
phalins, k receptors dynorphin and E receptors b-endorphin. hypothalamus, periaqueductal grey matter, nucleus of the trac-
With the synthesis of selective receptor antagonists, a family tus solitarius, amygdala, striatum, hippocampus and spinal
of three receptors that incorporates the previous classification cord. Functions related to pain regulation, motor activity,
has been identified according to their specific binding proper- feeding and response to stress have, among others, been pro-
ties to m opioid peptides (MOP), d opioid peptides (DOP) and posed for dynorphin. Activation of the KOP receptors by
k opioid peptide (KOP). These receptor peptides have been dynorphin often produces actions opposite to those of MOP
cloned. Knockout of MOP receptors eliminates morphine opioid receptors. For example, dynorphins produce aversive
actions but does not affect DOP- or KOP-mediated analgesia. reactions instead of the typical reinforcing actions of opioids.
MOP opioid receptors are found in the periaqueductal grey Increased dynorphin expression mediated by CREB appears
matter, the nucleus raphe magnus and the locus coeruleus, to be associated with aversive or depressive-like effects, such
among other brainstem regions involved in antinociception. as those that accompany drug withdrawal.
These cells give origin to descending fibres to reticular forma-
tion and spinal cord. Opioid receptors are found in the thala- Activation of dopamine D1 receptors stimulates a cascade
mus, amygdala and striatum, limbic areas involved in the of events that ultimately leads to CREB-mediated alterations
control of motivation. In the brain, there are two nuclei that in gene expression, notably the activation of expression of
contain POMC neurons – the arcuate nucleus of the hypothal- prodynorphin mRNA. Dynorphin peptide and gene expression
amus and the nucleus of the tractus solitarius – with associated are activated in the striatum, ventral striatum and amygdala
projections widely distributed. ProEnk-containing neurons are during acute and chronic administration of cocaine and alco-
also distributed throughout the brain in local and projection hol. The fact that stress increases dynorphin activity suggests
neurons. a potential interaction with corticotropin-releasing factor.

The physiological role of endogenous ligands for opioid Neuropetides and stress
receptors is still the subject of intense research. They appear
to be involved in the perception of pain and the neural control In response to stress, the pituitary gland secretes ACTH,
of certain aspects of endocrine function, the regulation of which in turn leads to increased synthesis and release of
movement, mood and some aspects of behaviour. When cortisol (corticosterone in rodents) from the adrenal gland.
opium, morphine, heroin and related drugs are ingested they

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Neuropharmacology CHAPTER 3

Two neuropeptides synthesised in the paraventricular nuclei of Mammalian bombesin-related peptides, gastrin-releasing
the hypothalamus – corticotropin releasing factor (CRF) and peptide and neuromedin B, act on three G-protein-coupled
vasopressin – are the key neuropeptides accounting for periph- receptors (BB1-3). Immunohistological results indicate that
eral increase of stress hormones. These neuroendocrine activ- these peptides are located among other areas in hypothalamus,
ities are closely associated with a large number of other olfactory bulb and dentate gyrus. Their receptors are found
neural projections resulting in release of CRF in amygdala, mainly in cortex and suprachiasmatic and supraoptic nuclei.
hippocampus, locus coeruleus and prefrontal cortex. CRF These peptides suppress food intake, are released in response
is a neuropeptide with two receptors, CRF1 and CRF2. Immu- to stress and have been associated with altered anxiety and
noreactivity to CRF has also been observed in amygdala, sep- depressive-type symptoms. For example, BB2 receptor stimu-
tum, nucleus accumbens, cortex and thalamus, among other lation facilitates memory and social interaction in rats, while
structures, and stress-induced alterations in its function may mice with a targeted disruption of bombesin receptor sub-
contribute to the pathogenesis of depression. Elevated concen- type-3 develop anxiety, hyperphagia, obesity, hypertension
trations of this neuropeptide in the hypothalamus and in the and impaired glucose metabolism (Yamada et al 2002). The
cerebrospinal fluid have been observed in depression and anxi- neural mechanisms underlying the effects of chronic stressor
ety disorders (Carpenter et al 2004). Considerable evidence exposure on these peptidergic systems has not been well
supports the view that excessive corticosteroid secretion defined but it has been proposed that alterations in bombesin
endangers neurons in the hippocampus, amygdala and receptors may be important in schizophrenia, Parkinson’s dis-
prefrontal cortex, by increasing their vulnerability to oxidative ease, anxiety disorders, anorexia, bulimia and mood disorders
stress and noxious agents, such as excitatory amino acids. The (Jensen et al 2008).
majority of patients with acute depression show an exagger-
ated plasma corticotropin that normalises in the course of anti- Ghrelin is an endogenous ligand of a receptor discovered by
depressant therapy. One antagonist of the CRF1 receptor has its ability to bind synthetic peptides and induce growth hor-
been tested for therapeutic efficacy in depression with positive mone release. These synthetic peptides were called ‘secretago-
results, though hepatotoxicity ended its further develop- gues’. Blood-circulating ghrelin is produced in the stomach,
ment. Both CRF1 and CRF2 antagonists administered together while neurons producing it are found in the hypothalamus,
intracerebroventricularly, or CRF1 antagonists alone, blocked with receptors mainly expressed in the nucleus of the tractus
stress-induced reinstatement of cocaine, opiates, alcohol and solitarius, ventrotegmental area, nucleus accumbens and amyg-
nicotine, reinforcing the hypothesis that the major driving dala. Peripheral and central administration of ghrelin stimu-
force in chronically relapsing drug addiction behaviours is lates growth hormone release, an avid appetite and weight
stress (Koob 2008). gain in humans and rodents. Similar to growth hormone-
releasing hormone, ghrelin also promotes slow-wave sleep in
Urocortins 1-3 are neuropeptides with an elevated sequence humans. Ghrelin plasma levels are increased in active alcohol
homology with the corticotropin-releasing factor. Urocortin 1 drinkers and alcoholics. Its participation in consummatory
binds to CRF1 and CRF2 receptors and urocortins 2 and 3 bind behaviour, addiction and stress-induced eating behaviour is
to CRF2 receptors. Very high production of urocortins is under study.
observed in the Edinger–Westphal nucleus, the accessory
nucleus of the third oculomotor nerve, and they are also found Cholecystokinin is a neuropeptide found, among other areas,
(in a smaller concentration) in hypothalamus and substantia in amygdala, thalamus, hypothalamus, hippocampus, striatum
nigra. In the human brain, urocortin immunoreactivity and and cortex. It has two major G-protein-coupled receptors –
mRNA is seen in hypothalamus, pons, cerebral cortex and CCK1, primarily found in the gastrointestinal tract, and
cerebellum. In the monkey, immunoreactive fibres have also CCK2 in the brain. Some three decades ago, it was reported
been observed in the amygdala and septum. The most signifi- that intraventricular administration of cholecystokinin pro-
cant action of urocortins is a potent suppression of food intake duced satiety and anxiety in sheep, two consequences of cho-
mediated by CRF receptors. An increase in urocotin mRNA lecystokinin receptor stimulation that have been repeatedly
has been reported following stress in animal models. confirmed (Wang et al 2005). Although great advances have
been made in understanding the mode of action of this neuro-
Nociceptin/orphanin FQ is a neuropeptide related to dynor- peptide, the production of selective agonists for the control of
phin that is characterised by its lack of binding to classical opi- obesity and antagonists for the control of anxiety and panic
oid receptors. The nociceptin/orphanin FQ receptor (NOP) is disorders has so far not proved successful. A better under-
a G-protein-coupled receptor expressed widely in serotoniner- standing of the interaction of cholecystokinin with other neu-
gic, noradrenergic and dopaminergic neurons, with actions rotransmitter systems will be needed before further
that are presumably inhibitory. Its distribution suggests its par- development can be achieved in this field (Berna et al 2007).
ticipation in regulating responses to stress, anxiety and depres-
sion. Intracerebroventricular administration of nociceptin/ It is comforting to know that some neuropeptides counter-
orphanin FQ has anxiolytic effects and reduces ethanol con- act the effect of stress, one being neuropeptide Y. NPY is one
sumption in a strain of alcohol-preferring rats. Knockout mice of the most abundant neuropeptides in the central nervous sys-
for the gene coding the neuropeptide tend to be more suscep- tem and is co-localised with noradrenaline in peripheral auto-
tible to developing stress and fear/anxiety behaviours. The nomic and sensory neurons, in the medulla, locus coeruleus
use of specific antagonists and genetic findings suggest that and nucleus of the tractus solitarius. Three receptors modulate
blockade of nociceptin/orphanin FQ signalling results in NPY responses in the brain, their stimulation producing anti-
antidepressant actions (Gavioli & Calo 2006). anxiety effects. NPY overexpression in the amygdala in rats,
produced by a viral vector containing NPY complementary

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Companion to Psychiatric Studies

DNA, results in anxiolytic effects and decreased alcohol con- these dopamine receptors. The neuromodulatory effects
sumption (Thorsell et al 2007). In humans, plasma levels of of neurotensin on dopamine transmission have made it an
NPY correlate with enhanced stress resilience (Morgan et al appealing target for therapeutic approaches.
2000). A decrease in basal NPY-like immunoreactivity is
observed in animal models of depression and increases in Substance P belongs to the neurokinin family of neuropep-
NPY have been reported following antidepressant use in both tides and exerts its biological effects via interaction with the
animals and humans and the production of NPY receptor ago- NK1 receptor (Stout et al 2001). Substance P immunoreactiv-
nists and antagonists with clinical applications in depression ity is observed in spinal cord, substantia nigra, ventral tegmen-
and alcohol dependence has become an important challenge tal area, striatum, cortex, amygdala and locus coeruleus among
(Eaton et al 2007). other areas. In the rat, it is co-localised with serotonin. NK1
knockout mice display reduction in anxiety and stress-related
VGF (non-acronymic) is a neuropeptide expressed in brain behaviours. Antagonists to this receptor also have some anti-
neurons including thalamus, hippocampus, cortex and striatum depressant efficacy but treatment-limiting side-effects have
and endocrine cells in the adenohypophysis, adrenal medulla, so far precluded drug development.
gastrointestinal tract and pancreas. It has been reported to
enhance hippocampal synaptic activity and learning (Alder Galanin is a neuropeptide coexpressed in neurons with
et al 2003). Exercise increases VGF expression and release in noradrenaline, serotonin and acetylcholine. Its effects are
the hippocampus (Hunsberger et al 2007) while VGF induces mediated by three different G-protein-coupled receptors
an antidepressant response in behavioural mice models, which (GalR1-3). Galanin has neuromodulator functions within cen-
is consistent with its increase observed following electro- tral and peripheral nervous systems and has been demon-
convulsive shocks in rats (Thakker-Varia & Alder 2008). This strated to participate in various complex functions, such as
neuropeptide could mediate the antidepressant effects of nociception, the sleep/wakefulness cycle, and in neuroendo-
exercise and is another potential therapeutic target for drug crine activities associated with feeding, energy metabolism,
development. thermoregulation, osmotic and water balance, and reproduc-
tion. Human autopsy studies in Alzheimer’s disease have
Prolactin-containing cells are found in the paraventricular observed increased galanin receptor expression and galanin-like
nucleus of the hypothalamus and prolactin-like immunoreac- immunoreactivity which could be associated with cholinergic
tive fibres are observed in the amygdala and bed nucleus of cell death. Recently, interesting results have been obtained
the stria terminalis. Prolactin, in addition to its role during with genetic techniques, such as receptor knockouts and gala-
lactation and in maternal behaviour, seems to decrease the nin overexpressing transgenic animals. A role in neuroprotec-
release of ACTH and its associated emotional responses. tion and epileptic seizures has been associated with GalR1,
Increasing prolactin by intraventricular administration pre- while a single nucleotide polymorphism in the gene coding
vented stress and showed antidepressant activity in animal for the GalR3 has been associated with the risk of alcoholism.
models. Similarly, downregulation of the expression of prolac- In addition, antidepressant treatment (fluoxetine  14 days)
tin receptors has been reported to increase anxiety-related appears to increase galanin mRNA and GalR2 receptor binding
behaviour (Torner et al 2001). Furthermore, neuroendocrine levels in the serotonin-containing neurons of the dorsal raphe
stress responses and anxiety scores are attenuated in states of nucleus. It is not surprising that drug companies are aiming
hyperprolactinemia and during lactation in various species, for the development of galanin receptor agonists and antago-
including humans (Asher et al 1995). nists that may be of value in the treatment of Alzheimer’s dis-
ease, depression and alcohol addiction (Mitsukawa et al 2008;
Neuropeptides as targets in drug discovery Picciotto 2008).

Among the neuropeptides directly targeted so far in the devel- Two striking discoveries
opment of drugs for the treatment of psychiatric illness are
neurotensin, substance P and galanin. Neuropeptide research has contributed to our understanding
of the origin of narcolepsy and the underlying mechanisms of
Neurotensin is a tridecapeptide present in the hypothala- affiliative social behaviour.
mus, amygdala, bed nucleus of the stria terminalis, lateral
septum, nucleus accumbens, striatum and ventral tegmental The orexins (also known as hypocretins) are two neuro-
area. It is co-localised with dopamine in mesocortical neu- peptides – orexin A (hypocretin1/hcrt1) and orexin B (hypo-
rons but not in nigrostriatal or mesolimbic neurons. Three cretin2/hcrt2) – produced in the perifornical area of the
G-protein-coupled receptor subtypes which activate phos- lateral hypothalamus. Orexin neurons project to dorsal raphe,
pholipase C have been described for this neuropeptide. locus coeruleus and ventral tegmental area. Their function is
Neurotensin modulates neurotransmission in areas where it is mediated by two G-protein-coupled receptors, OX1 and
released – e.g. in the nucleus accumbens it acts on receptors OX2. A major function of the orexins was evidenced when
located on glutamate terminals and induces enhancement of positional cloning revealed that a recessive mutation was asso-
glutamate release – and a potential antipsychotic action has ciated with narcolepsia in dogs (Lin et al 1999). Narcolepsy in
been proposed based on its ability to antagonise dopamine humans is a chronic neurological disorder characterised by
D2 receptors (Antonelli et al 2007). Neurotensin also interacts intrusions of rapid eye movement (REM) sleep into wakeful-
with the dopoamine D1 receptor by delaying or diminishing ness and postmortem analysis of brain tissue from patients
sensitisation to psychostimulant drugs regulated primarily by suffering from this disease subsequently revealed a significant

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Neuropharmacology CHAPTER 3

decrease in orexin-producing neurons (Peyron et al 2000). and the coordination of glial responses to damage (see section
Orexin neurons discharge maximally during active wakefulness ‘Steroid and thyroid hormone-like receptors’ above).
and cease discharge during sleep, including REM sleep. A loss
of orexin neurons has been observed in Parkinson’s disease, Nerve growth factor (NGF) was the first trophic factor
which could account for the sleep problems associated with to be identified. All neurotrophic factors have similar charac-
the disease (Sakurai 2007). teristics and are synthesised as precursor proteins. Other
neurotrophins include neurotrophins 2 and 3 (NT2, NT3),
Oxytocin and vasopressin form the nine amino acid ‘nano- brain-derived neurotrophic factor (BDNF), glial cell line-
peptide’ family. These neuropeptides are primarily synthesised derived neurotrophic factor (GDNF) and neurotrophin 4. Neu-
in the preoptic area and anterior hypothalamus. Apart from the rotrophins bind to two types of cell membrane receptors – the
hormonal secretion from the posterior pituitary into the sys- tropomyosin-related kinase (Trk) family of receptor tyrosin
temic circulation, neuronal projections release nanopeptides kinases, and the p75 neurotrophin receptor.
into several brain areas. Additionally, cells in the medial bed
nucleus of the stria terminalis and medial amygdala also synthe- BDNF is widely distributed in the central nervous system.
sise vasopressin. Nanopeptide-containing cells mainly project Most of what is known about it relates to those functions
to the lateral septum, ventral pallidum, olfactory tubercle, lat- mediated by TkrB receptors, the main one of which is regula-
eral habenula, dorsal raphe, locus coeruleus and hippocampus. tion of synaptic plasticity. The transcription of this factor
Male rats have 2–3 times more arginin-vasopressin cells than is regulated by glutamate, GABA and acetylcholine, while
females, with circulating gonadal steroids thus driving the the neurotrophin itself enhances activity-mediated neurotrans-
expression of these neurons and their postsynaptic targeting. mitter release and, postsynaptically, enhances N-methyl-D-
The oxytocin receptor (OXTR) and the three vasopressin aspartate receptors. Hippocampal long-term potentiation
receptor subtypes (V1a, V1b and V2) are G-protein-coupled upregulates BDNF mRNA, and the BDNF by itself can induce
receptors. a glutamate-independent form of long-term potentiation
(Messaoudi et al 1998). This neurotrophin shapes axonal
Consistent results support the idea that nanopeptide recep- terminal fields and dendritic arborisations (Danzer et al
tor stimulation promotes affiliative behaviour and inhibits 2002). Reduced mRNA expression and BDNF concentration
aggression. Indeed, oxytocin has been labelled the ‘social has been observed in postmortem analysis of Alzheimer’s
neuropeptide’ because of its ability to regulate social recogni- patients and, while a similar decrease in Parkinson’s disease
tion and affiliation and its modulation of anxiety, mood and could reflect simple loss of neurons, the surviving neurons in
aggression. Thus, in humans, intranasal oxytocin facilitates substantia nigra also express less BDNF (Howells et al
‘trust’ behaviour as measured in a computer game, and the 2000). It has recently been proposed that direct supply of
ability to detect subtle emotional cues from pictures of eyes. BDNF into the caudate-putamen of Parkinson’s disease
Vasopressin on the other hand, has been implicated in several patients could promote survival of dopamine terminal fields,
male-typical social behaviours, including aggression, scent while intracerebral delivery of the more potent neurotrophic
marking and courtship, with vasopressin V1b receptor knock- factor – glial cell line-derived neurotrophic factor (GDNF) –
out reducing aggressive behaviour in male mice. Oxytocin could have similar neuroprotective effects (Lindvall &
knockout mice fail to recognise individuals to which they have Wahlberg 2008). BDNF levels have also been correlated with
been previously exposed while infusions of oxytocin into the expression of CAG repeats from the mutant huntingtin,
the medial amygdala completely restore social recognition. associating BDNF with another neurodegenerative disorder,
Dopamine administration induces central oxytocin release, Huntington’s disease (Canals et al 2004). Furthermore, a
whereas oxytocin administration increases central dopamine change in BDNF has been associated with the development
levels in the rat. Since oxytocin and vasopressin participate in of depression and with antidepressant treatment. Acute and
social recognition and they interact with dopamine, which chronic stress decreases the expression of BDNF mRNA and
assigns a relevant mark to stimuli (‘salience’), it has been serotonin reuptake inhibitors elevate the transcript levels in
proposed that pair-bonding results from the convergence of animals (Martinowich & Lu 2008).
oxytocin and vasopressin under the reinforcing properties
of dopamine. The modulatory role of nanopeptides in a variety Neuronally produced gases
of behaviours related to stress, and possibly drug addiction,
make their genetic promoters and receptors promising targets The most recent puzzle in neurochemistry is the discovery
for future therapeutic interventions (Neumann & Landgraf that some neurons possess the enzymatic machinery to pro-
2008). duce gases. The best-studied example is the enzyme called
nitric oxide synthase (NOS). This is one of a family of NOS
Peptide regulatory factors enzymes which occur in various sites in the body. The best
known is perhaps the NOS of macrophages that may be
CNS peptide regulatory factors are not the same as neuropep- involved in cell killing in the immune system. But why would
tides. They act through a different class of receptors and are neurons have evolved such a potentially lethal cargo? It seems
important in the normal development of the nervous system, that there are soluble GTPases in neurons that are appropriate
when they are usually called neurotrophins. These trophic receptors for nitric oxide (NO), formed when arginine is
substances are also important in neurodegenerative diseases, converted to citrulline by NOS. NOS enzymes utilise the
as they are necessary for the restoration of neural circuits amino acid, L-arginine, and molecular oxygen to produce the

73

Companion to Psychiatric Studies

free-radical gas *NO (a free radical is a group of atoms that has between NO and blood flow control has recently been invoked
at least one unpaired electron, hence the asterisk, and is unsta- as at least one important function in the cerebral cortex where
ble and highly reactive). The free-radical gas, *NO, functions direct activation of NOS-containing neurons was shown to
as a regulator of vascular homeostasis, neurotransmission and change blood flow in local capillaries (Tong & Hamel 2000).
host defence. The lifetime of this gas is limited by the scaveng-
ing reactions involving haemoglobin and other radicals. Endog- S-nitrosylated proteins form when a cysteine thiol reacts
enous NO metabolism produces nitrite and nitrate as inert with NO, a post-translational modification that affects the
oxidative products, which are in turn recycled in blood and tis- function of a wide array of neuronal proteins, including the
sues to form NO by a process not requiring oxygen. The gen- enzyme, caspase 3, and two subunits of the NMDA receptor.
eration of NO by nitrite and nitrate is enhanced during These NO-induced changes lead to less Ca2þ influx through
hypoxia and acidosis which contributes to the physiological the receptor with subsequent decreases in neurotoxicity and
response to ischaemic stress (Lundberg et al 2008). changes in synaptic plasticity.

NO acts as a neurotransmitter by acting on NO intracellular Carbon monoxide (CO), which also acts as a neurotransmit-
receptors. The NO receptor is a soluble guanylyl cyclase ter, binds soluble guanylyl cyclase equipped with haem ligand
equipped with a ligand site or haem group, a dimerisation sites and stimulates the production of cGMP. CO is produced
domain and a catalytic domain for the transformation of by heamoxygenase, a microsomal enzyme that produces
GTP into cGMP. This neurotransmitter is localised in the biliverdin and CO. Among the effects of CO are vasorelaxa-
hypothalamus, where it seems to ‘fine-tune’ the release of tion, inhibition of proliferation of smooth muscle cells, protec-
CRF and vasopressin (Calabrese et al 2007). As a neuroprotec- tion of transplants from rejection, inhibition of platelet
tant, its effects are mediated through several second messen- aggregation, influences on apoptosis, anti-inflammatory actions
ger cascades. Thus, it induces activity of the haem oxygenase and actions on neurotransmission. CO reduces intracellular
1 which generates biliverdin, the precursor of the powerful Ca2þ by several mechanisms, such as binding guanylate cyclase
antioxidant bilirubin, and activates cAMP responsive element and increasing cGMP levels and modulation of KCa2þ channels,
binding protein (CREB) and Akt, two neuroprotectant pro- as well as by ‘cross-talk’ with NO or by blocking the expres-
teins. The fact that the cells in the caudate–putamen which sion of cytokines (Mannaioni et al 2006).
produce NO are the last to die in Huntington’s disease has
led to the suggestion that they may cause at least some of The actions of these cellularly generated gasses presents just
the neurotoxic damage in that condition. one of the many challenges facing us in the continued battle to
understand enough of the neurochemistry and neuropharma-
Endothelial cells also generate an NOS which is thought to cology of the brain to be able to help alleviate the symptoms
provide vasodilator tone in the CNS. The close association of psychiatric disorders.

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76

Neuroimaging 4

J Douglas Steele Stephen M Lawrie

Introduction sulci, with progression in chronic cases, proved to be widely
replicated findings (Lawrie et al 2004), but the risks and dis-
Psychiatric disorders are associated with disturbances of brain comfort meant that pneumoencephalography could not be used
structure and function. This fact, although not remarkable in extensively.
itself, has taken the best part of 30 years of work to gain wide-
spread acceptance. We have an ever increasing array of sophis- X-ray computerised tomography (CT)
ticated and complementary neuroimaging methods with which
we can study the brain/mind in vivo, and the now substantial CT was developed in 1971 (Hounsfield 1973), and clinical
imaging literature on many psychiatric disorders has generated studies began soon after. In the first use of the technique in
several replicated findings. Refinements of techniques and patients with schizophrenia, the outline of the ventricles and
their application to particular populations will likely provide the brain were traced onto graph paper and the ventricle: brain
further insights into the pathophysiology of these disorders ratio (VBR) was calculated and compared with controls
in the coming years. Some procedures are now finding routine (Johnstone et al 1976). CT images are obtained from the
clinical application in certain conditions and are increasingly reconstruction of X-ray transmission from multiple projections
used to facilitate the development of new treatments. In this around the object of interest. The X-rays are detected using
chapter we will briefly describe the principal neuroimaging various methods, including sodium iodide crystals and photo-
methods currently used, summarise the best replicated and multiplier tubes. A major limitation of CT scanning arises from
most promising findings in particular disorders, consider the the absorption of lower-energy X-ray photons as they pass
most likely clinical applications and finally address important through tissue, so that the beam becomes composed of
general issues. Only an introduction to these matters can be higher-energy rays (‘beam hardening’). The effect is loss of
provided here. For more detail the reader is referred to other contrast next to bony structures, such as in the temporal lobes
texts (Moonen & Bandettini 2000; Frackowiak et al 2004; and posterior fossa. CT also has relatively poor spatial resolu-
Lawrie et al 2004). tion and thus does not provide detailed information on regional
brain abnormalities. These methodological problems mean that
Structural brain imaging techniques CT is now of limited research value in comparison with struc-
tural MRI (Table 4.1), but it is still commonly used in clinical
The first attempts at imaging brain structure in vivo were con- neurology settings: to detect space-occupying lesions, in the
ducted using pneumoencephalography. After lumbar puncture, differential diagnosis of stroke and to identify some treatable
cerebrospinal fluid (CSF) was withdrawn and replaced with a causes of dementia. A number of macroscopic abnormalities
gas, usually air, to outline the cerebral ventricles and cortical (e.g. usually benign tumours, cysts, vascular malformations)
surface using X-ray roentgenography. The technique was first are occasionally found in psychotic patients – with a preva-
applied to psychiatric patients by Jacobi & Winkler in 1927, lence of approximately 5–10% – but these appear to have no
who described an apparent loss of brain tissue in schizophrenia. specific relationship to particular disorders, are as often devel-
Enlarged lateral and third ventricles, as well as widened cortical opmental as acquired and rarely change medical management
(Lawrie et al 1997).

ã 2010, Elsevier Ltd.
DOI: 10.1016/B978-0-7020-3137-3.00004-8

Companion to Psychiatric Studies

Table 4.1 Comparison of X-ray CT and structural MRI repeatedly apply RF pulses as spatial information is encoded
using magnetic gradients in three dimensions. The time
CT MRI between each pulse is called the repetition time (TR).

Maximum number of Limited by radiation No limit T1 image contrast
examinations dose
Soft tissue contrast 1–2% 100–200% Following the RF pulse, transverse magnetisation returns
Spatial resolution >1 mm <1 mm towards the longitudinal plane (axis of B0) over a period of
Imaging plane As patient position Any time known as the T1 relaxation time (Fig. 4.2A). This period
Bone signal Strong Low is also known as the spin-lattice or longitudinal relaxation
Posterior fossa visibility Poor Good time. T1 differs between tissues, the extent of such differ-
ences depending upon a choice of image acquisition para-
Structural magnetic resonance meters, leading to image contrast. For any two tissues with
imaging (sMRI) different T1s, there is an optimal TR that produces best image
contrast; and for any given TR there is an optimal flip angle,
which maximises signal strength. Clinically, T1 images provide
good grey-white matter contrast and therefore anatomical
information.

MRI uses signals from protons – usually the hydrogen nucleus T2 image contrast
in water. An isolated proton can be considered as a charge
rotating about a randomly orientated axis (Fig. 4.1A). When Tilting M results in a rotational component in the xy plane,
an external magnetic field (B0) is applied, the axis of rotation which is called an echo. Initially, all the proton axes are essen-
(p) aligns along the axis of the field but rotating about it (see tially rotating together (in phase) but begin to rotate at dif-
Fig. 4.1B). This rotation is termed precession or resonance. ferent speeds (dephasing), resulting in a loss of transverse M
The resonance frequency is related to magnetic field strength and therefore signal over a period termed T2 or the ‘transverse
(B0). There is a tendency for a net alignment of protons along magnetisation time’ (see Fig. 4.2B). This period is also known
the magnetic field, and they produce their own magnetic fields as the spin-spin relaxation time. Note that T2 is less than or
to produce a measurable signal (M). Only the component of M equal to T1. The interval between the creation of transverse
at right angles to B0 (in the transverse xy plane) is measurable, magnetisation and its measurement is the echo time (TE).
so it is necessary to temporarily tilt (or flip) M away from B0 Only some tissues exhibit differences in T2, but an optimal
by brief application of a resonant radio-frequency (RF) pulse TE exists for those and provides the best image contrast.
(see Fig. 4.1C). The magnitude of this effect is referred to as T2-weighted images are particularly useful for imaging
the flip angle. To obtain an image, it is usually necessary to pathological processes in the brain, including white matter
hyperintensities, demyelination, infarction and haemorrhage.

A z B0
p B

z B0
p T1

M

C z B0 x yy
p Ax

(i) (ii) (iii)
z B0 z B0 z B0

pxy y pxy pxy y
x x y
pxy y B
x
x
Fig. 4.1 (A) Proton represented as a spherical rotating charge Fig. 4.2 (A) T1 relaxation time: time for M to realign with z axis;
with axis p; (B) precession of p about z due to B0; (C) tilt of p by (B) T2 relaxation time: dephasing of pxy from (i) to (iii), causing loss
external radio-frequency pulse. of signal Mxy.

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Neuroimaging CHAPTER 4

T2* images Creatine/ N-acetylaspartate
phosphocreatine
If the applied magnetic field varies from proton to proton,
protons exposed to higher magnetic fields resonate faster, Choline
and vice versa. This causes dephasing and accelerated loss of
transverse magnetisation (and therefore signal). Such magnetic 4.0 3.0 2.0 1.0
field variation can be due to air-containing cavities in the head, Parts per million
such as frontal sinuses and ear canals. As the head has different
magnetic properties to air, the cavities create magnetic fields Fig. 4.3 Magnetic resonance spectrum. (Courtesy of Professor
(termed ‘susceptibility’) in adjacent brain tissue. The conse-
quence is signal loss and displacement in regions such as the I Marshall.)
orbitofrontal cortex, adjacent subgenual anterior cingulate
and inferior temporal lobe, known as the ‘susceptibility arte- Table 4.2 Some nuclei commonly used in magnetic resonance
fact’. Methods are available, however, to reduce the signal loss spectroscopy
(Lipschutz et al 2001).
Nucleus Use
Diffusion tensor imaging
19F Labelled drugs
Water is ubiquitous in biological tissue and is constantly in 1H Glutamate, lactate, choline, creatine
random Brownian motion. Such movement is constrained by 7Li Allows monitoring of lithium treatment
anatomical structures such as fibre tracts. Using MRI, it is 23Na Intra- and extracellular measurement
possible to measure water molecule diffusion in three dimen- 13P ATP/ADP energy measurement
sions in each voxel (volume element). This ‘diffusion tensor
imaging’ (DTI) technique produces summary measures of cerebral aneurysm clips or metallic fragments from an acci-
mean diffusion and non-random movement (‘fractional anisot- dent, because the strong magnetic fields can displace metal.
ropy’). These can be presented as a variety of images, allowing Otherwise MRI is safe and can be repeated several times with-
inferences about the integrity of structural connections. One out known risk. The combination of high spatial resolution,
display method is an ‘ellipsoid plot’, where the extent and improved soft tissue contrast and absence of ionising radiation
direction of diffusion at each voxel is shown. Other ‘tractogra- means that MRI has replaced CT for research work and is
phy’ techniques allow ‘surface rendering’ of fibre tracts, i.e. preferred for most routine clinical work.
viewing tracts constructed as solid objects in relevant parts
of the brain. While these techniques are visually appealing, Functional brain imaging techniques
any structural abnormalities of connections in psychiatric dis-
orders are (almost by definition) likely to be subtle and require Functional brain images are indirect measures of neuronal
quantitative analysis. activity, as indexed by blood flow and metabolism. Generally
it is assumed that increased blood flow is a response to the
Magnetic resonance spectroscopy (MRS) increased metabolic demand of active neurons, although the
molecular mechanisms associated with these demands remain
In a molecule, nuclei are shielded from an external applied unclear. Many different neuronal operations, including synap-
magnetic field (B0) by the electron cloud of other atoms. tic excitation, synaptic inhibition, neuronal soma action poten-
This shielding also creates small additional magnetic fields tials and subthreshold depolarisation, are translated into
characteristic of an atom’s position in the molecule. This dif- just one dimension of metabolic and haemodynamic response
ference in magnetic field causes a shift in resonance frequency, according to energy need. Both inhibitory as well as excit-
which can be measured and presented as a magnetic resonance atory events may induce increased energy need (Moonen &
spectrum (Fig. 4.3), allowing identification of certain bio- Bandettini 2000). Thus, functional brain images are ambiguous
chemicals. Table 4.2 lists some of the more commonly used with regard to the underlying neurophysiological events.
nuclei in MRS and their biological significance. Current limita- A region of a functional image that is ‘activated’ may reflect
tions of MRS include relatively poor spatial resolution with inhibitory and/or excitatory neuronal events. ‘Deactivation’
consequent partial volume effects, long data acquisition times of a region reflects a lack of both categories of neuronal events,
and the susceptibility artefact. relative to the comparison condition. Fortunately, although the

MRI techniques are all sensitive to subject movement, due
to image acquisition times of several minutes, and this can
cause image blurring. Various methods, including head
restraint, and cardiac and respiratory ‘gating’ (i.e. only acquir-
ing images at the same point in the cardiac or respiratory
cycle) can, however, help. MR scanners tend to have particu-
larly enclosed environments, and there is considerable noise
generated by the pulse sequences, which some patients do
not like. Subjects must be excluded from MRI studies if they
have implanted metallic objects, such as a cardiac pacemaker,

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Companion to Psychiatric Studies

principal functional imaging techniques differ in how they Contemporary machines use a rotating gamma camera with
assay neuronal activity, very similar results have been obtained multiple detectors, which can generate contiguous brain sec-
when similar questions have been addressed (Frackowiak et al tions with good resolution. Gamma cameras are composed of
2004). a lead collimator with a sodium iodide crystal. The origin of
the single gamma rays emitted by the radiotracer is calculated
Single photon emission (computed) from their trajectory through parallel holes in the collimator,
tomography (SPECT) which only lets photons from a certain direction through,
absorbing the others and thereby ‘focusing’ the detection.
Kety and Schmidt were the first to develop, in 1948, a feasi- The sodium iodide crystal scintillates (produces small flashes
ble method of in vivo examination of putative ‘metabolic of light) on contact with gamma rays; the light signals are then
derangements’ of the brain. They used invasive measures of amplified by photomultiplier tubes and recorded.
nitrous oxide, as a diffusible inert index of arterial and venous
blood flow (brain uptake being the difference between the After acquisition, the data are processed with a ‘filtered
two), but could only examine global cerebral blood flow and back-projection’ technique. Excessive or inadequate filtering
oxygen consumption and did not find any differences between will reduce image resolution. Signal attenuation is corrected
patients with schizophrenia and normal controls. In contempo- by reference to a model, which assumes scatter is homoge-
rary SPECT imaging, a radioactive tracer substance is adminis- neous within an ellipsoid brain. Reconstructed axial sections
tered intravenously, with minimal environmental stimulation can then be displayed, which can be qualitatively assessed
(sometimes with ears and eyes patched) and subjects are asked (as in radiology) or further processed for quantitative analysis
to remain physically inactive during the equilibration period. (as in psychiatric research). Methodological artefacts may arise
Most research studies now include some type of sensory, motor as a result of differences in scanning protocol. Even having
or cognitive activation paradigm, or pharmacological stimula- the eyes open or closed may alter the signal, and the more
tion, as the main purpose of the study. For routine clinical ‘physiological’ condition of eyes open may give more reproduc-
studies, such paradigms or stimulation are not usually used. ible results as long as stimulation is minimised. The spatial
resolution with SPECT is limited, compared with PET,
Radiopharmaceuticals for SPECT are of four main types, by scattering and collimator performance; SPECT also has a
all of which emit a single gamma ray per nuclear disintegra- tendency to overestimate high blood flows (especially in
tion. Dynamic or diffusible indicators, such as inhaled 133Xe white matter) and an insensitivity to small activity differences
(10 mCi/minute), are relatively cheap and can give absolute at high perfusion, leading to limited grey-white matter
or quantitative regional cerebral blood flow (rCBF) values resolution.
(in ml/min/100 g brain tissue) as long as tracer input is measured.
However, their low energy (80 keV) limits resolution and Nonetheless, the latest SPECT systems have a resolution
inferior frontal regions can be contaminated by inhaled gas approaching that of PET and ligand studies of neuroreceptor
in the nasal passages and cause a false ‘hyperfrontality’. binding remain of great research interest. Further, because
123I-labelled lipophilics, such as IMP (123I N-isopropyl p- the tracer acts like a tag delivered to brain tissue and remains
iodoamphetamine), generate high-energy gamma rays (159 keV) there for some time, the SPECT image reflects the blood flow
with enhanced photopeak detection and resolution, but may distribution at the time of radioactive tracer injection, not
only accurately reflect rCBF for 60 minutes after injection. scanning (cf. PET and fMRI later). This can be a considerable
As with 123I-labelled neuroreceptor ligands (Table 4.3), they advantage in situations where it would be otherwise be impos-
are not widely used, as iodination requires an expensive cyclo- sible to do PET or fMRI scanning, e.g. during active physical
tron facility. 99mTc-labelled lipophilics, such as 99mTc-HMPAO exercise. Clinically, SPECT is particularly sensitive to some
(technetium-hexamethylpropyleneamineoxime/exametazime), pathology, including epileptic foci and arteriovenous malfor-
are widely available and extensively used as they have a similar mations, which are associated with altered blood flow and
distribution but are less expensive than 123I lipophilics. The metabolism. This is one of the very few current clinical uses
main problem with HMPAO is pronounced back-diffusion in of functional imaging. SPECT can also usefully inform the
high flow regions, which, combined with higher extraction differential diagnosis of dementia (Dougall et al 2004;
in low flow areas, can result in poor contrast. McKeith et al 2007). Qualitative visual inspection of scans is
unreliable except in the most dramatic cases, but clinical appli-
cations of quantitative methods have much potential (see
below).

Table 4.3 Commonly used receptor ligands for SPECT

Receptor Ligand Positron emission tomography (PET)

Muscarinic 123I Quinuclidinyl-iodobenzilate A PET scanner uses a ring of radiation detectors to produce
123I lomazenil
GABA 123I lodobenzamide (IBZM) images of the distribution of radio-isotopes in the brain, and
123I 2-b-carbomethoxy-3-b-(4-iodophenyl)-tropane
Dopamine D1/D2 (b-CIT) can measure cerebral blood flow (CBF), oxygen extraction
5HT/DA
transporter fraction (OEF), blood volume (CBV) and glucose metabolic

rate (CMRgluc).
Nowadays radio-isotopes are administered intravenously

and are labelled with one of four radionuclides – 11C, 13N,

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Neuroimaging CHAPTER 4

Table 4.4 Commonly used receptor ligands for PET Table 4.5 Comparison of SPECT and PET methods

Receptor Ligand SPECT PET

Muscarinic 11C-scopolamine Running Low (radiopharmacist) High (cyclotron)
Benzodiazepine 18F-flumazenil costs
Dopamine D2/D3 11C-raclopride Once or twice per session Up to 12 times per session
Dopamine D2/D3/D4 11C-3N-methylspiperone (NMSP) Repeatable Some tracers Yes
5HT2 11C-ketanserin and 18F-setoperone
Presynaptic dopamine synthesis 18F-fluorodopa rCBF Removed with energy filter Do not produce coincidence
quantifiable events

Scattered Modelled Empirical
photons

Attentuation
correction

15O or 18F. 15O has a half-life of only 2 minutes, allowing mul- Resolution 8–12 mm, limited by 2–3 mm, limited by distance
tiple and sequential scans in the same session, which makes it Compton scatter and between positron emission
ideal for activation studies. Specific functional anatomy can be Radiation collimator performance and annihilation reaction
discerned by comparison to baseline activity. energy Lower (75–160 keV) Higher (511 keV)
Tracer
In addition, PET can be employed to determine neuro- half-lives Long (6–13 hours) Short (2–110 minutes)
transmitter turnover, by administering a radioactive substrate
such as fluoro-dopa, and receptor quantification by a variety Functional MRI (fMRI)
of techniques involving labelled ligands (Table 4.4). In vivo
receptor density measurement can be undertaken by either The most common method of fMRI is blood oxygen level
single-dose tracer kinetics or saturation analysis at equilib- dependent (BOLD) fMRI, which uses the differential mag-
rium. In studies of dopamine receptors, kinetic studies use netic properties of deoxygenated and oxygenated haemoglobin
11C-N-methylspiperone (NMSP) or one of its analogues, while as an endogenous source of contrast, since the ferrous iron has
saturation experiments use 11C-raclopride. These techniques different magnetic properties depending on whether it is
can also be employed to estimate the receptor occupancy of bound to oxygen or not. This difference can be detected
different medications as used in clinical practice. by T2* imaging (although susceptibility artefacts may be pres-
ent). As discussed earlier, fMRI can detect metabolic and
The administered radio-isotopes are unstable, have an haemodynamic changes secondary to alterations in neuronal
excess of protons and emit positrons during radioactive decay. activity. The coupling between neuronal activity and haemo-
Positrons travel a distance of 1–3 mm before losing kinetic dynamic change is tight but slow (seconds) compared with
energy and colliding with an electron, with the consequent neuronal events (tens of milliseconds) and fMRI images are
emission of two gamma ray photons at approximately 180 ambiguous with regard to the underlying neurophysiological
degrees to each other. Coincidence detectors respond to two events.
simultaneous (within 5–20 ns) photons travelling in opposite
directions. The consequence is a finite limit on the ultimate Arterial spin labelling (ASL) fMRI
spatial resolution of PET (2–3 mm).
Arterial spin labelling is a promising alternative to BOLD
The brain image is reconstructed from a filtered back- fMRI. The ASL signal results from the delivery of magnetically
projection algorithm of all these coincidence lines, with filter- tagged water to the region of brain being imaged. Exchange of
ing (‘smoothing’) chosen to balance spatial resolution against arterial water with neuronal tissue is rapid but, because of the
statistical noise and edge effects. PET measurements of large tissue compartment, clearance is slower. As the ASL sig-
metabolism depend on the observation that the functional nal is localised to neuronal tissue of interest, in contrast to the
capacity of the adult brain is almost entirely dependent on predominantly venous BOLD signal, ASL may theoretically
oxidative glucose consumption (see Chapter 3). It should be provide better maps of functional brain activity. However,
noted however that the usual tight coupling between regional multislice ASL imaging is significantly slower than BOLD
cerebral blood flow (rCBF) and oxygen extraction is loosened fMRI (Moonen & Bandettini 2000).
in some acute diseases and by acute physiological stimulation.
The greatest limitations of PET are: (1) the tracers and ligands fMRI has the same general limitations as structural MRI,
require an on-site cyclotron for their manufacture, which is but is particularly sensitive to subject movement. One major
very expensive to install and maintain; (2) patients are exposed limitation of fMRI is that it is not possible to study ligand
to radioactivity, thus limiting the total number of scanning binding effects directly, although pharmacological manipula-
sessions for each subject; and (3) the temporal resolution of tions of the fMRI signal are possible. Like other functional
PET is poor compared to functional MRI. PET is therefore
likely to remain a research tool, with a prominent role in trans-
lational neuroscience (see later). A comparison of PET and
SPECT methods is summarised in Table 4.5.

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Companion to Psychiatric Studies

brain imaging techniques, fMRI is time consuming and expen- by the total brain counts (to form normalised counts). A major
sive, making the number of subjects in most published studies limitation of ROI-based analysis is ‘partial volume effects’
small. Repeated presentation of baseline and activation stimuli, as functional activation may occur in only part of an outlined
potentially hundreds of times for each subject, allows robust anatomical structure, and/or the estimated position of the
measurement of the small percent change in BOLD signal ROI might be slightly in error. The consequence of this
but cannot address intra-subject variability and limited study mismatch is reduced power of the statistical tests.
power consequent on relatively few subjects. Study power
estimation for fMRI is difficult due to the complexity of the Problems with partial volume effects and the need for fully
fMRI statistical model, but is crucial for proper study planning automated (relatively quick and objective) analyses have
and more work on power in fMRI studies is required. resulted in the development of voxel-based methods of image
analysis. The most popular method is Statistical Parametric
Quantitative image analysis Mapping (SPM, see http://www.fil.ion.bpmf.ac.uk/spm/),
developed by the psychiatrist Karl Friston, FRS and colleagues
Structural and functional brain abnormalities of interest in (Frackowiak et al 2004). SPM analysis typically follows a
psychiatric research tend to be subtle, requiring quantitative standard processing sequence:
analyses of imaging data obtained from groups of patients
and carefully matched controls. There are two general methods: 1. Scans in an imaging time series are realigned to each other,
pre-specified regions of interest (ROIs), and the voxel-based to correct for head movement during scanning.
image analysis.
2. Co-registration of the functional image to a structural image
Functional image analysis may sometimes follow.

Quantitative analysis of functional images can be done by 3. Spatial normalisation involves deforming the brain image
placing ROIs on (usually transverse) brain slices. Figure 4.4 from each subject so that it fits a standardised (template)
gives an example of such outlines. The average signal within brain image, to remove global differences in the size and
each region can then be calculated and analysed statistically, orientation of each ‘normalised’ brain and so that the same
for example with t-tests between two groups. In SPECT and anatomical regions in each image occupy the same voxels,
PET imaging, as the amount of radioactivity taken up by the with attendant reduced statistical variance and increased
brain is variable, these averaged counts are usually each divided power.

4. Spatial smoothing (blurring) of the image, which reduces
spatial resolution, is counter-intuitive but maximises the
probability of valid signal detection (Friston 2002; http://
www.fil.ion.ucl.ac.uk/spm/papers/spm-chapter.pdf).

5. The next stage is statistical analysis of the data, e.g. in the
comparison of two groups, to calculate a t-test statistic
for each voxel. Global brain functional activity is accounted
for using the general linear model (actually, multiple
linear regression) with global counts as a covariate of
no interest and dummy variables to indicate group
membership.

The resultant three-dimensional map of t-values, all at identi-
fiable locations in standardised space, is a ‘statistical para-
metric map’. (Note that SPM is not the only way of
producing such maps.) As there are typically tens of thousands
of voxels, the statistical tests are repeated many times, and
the likelihood of chance findings is high. A straightforward
Bonferroni correction is too conservative as adjacent voxels
are not independent measures, because of image blurring, and
a range of alternatives are possible (Friston 2002). Figure 4.5
shows an example of increased cingulate activation in controls
relative to patients with schizophrenia, when performing a task
in the scanner. The yellow coloured region indicates a collection
of voxels where brain activity differs significantly between
the two groups. This region has been superimposed onto a
structural T1 scan to assist interpretation.

Fig. 4.4 SPECT axial slice with region of interest (ROI) mask Structural image analysis
superimposed. ROIs include anterior cingulate gyrus (C and D),
dorsolateral prefrontal cortex (R and F), basal ganglia (J and K), ROI methods are still frequently employed in the analysis
occipital cortex (W and X). (Courtesy of Professor K Ebmeier.) of structural brain images. Typically, a detailed protocol
for identifying anatomical landmarks will be developed and
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Neuroimaging CHAPTER 4

Fig. 4.5 Statistical parametric maps
showing two regions of increased
activity in controls relative to patients
with schizophrenia.

then applied by one or more experienced operators to Functional integration
outline structures of interest, blind to subject details. The
method is very operator intensive and slow, but it remains The image-processing methods discussed above identify func-
the ‘gold standard’ for structural analysis. It is relatively tional segregation, i.e. functional specialisation within localised
straightforward to examine reproducibility by tests of inter- brain regions. Complementary methods are used to investigate
and intra-rater reliability. Variations of this approach may be functional integration. (Note that DTI is used to measure
used to examine the gyrification pattern of the cortex, or to structural connectivity.) Two concepts are relevant: functional
‘parcellate’, i.e. outline, very small regions in three dimensions and effective connectivity. Functional connectivity is defined
simultaneously. as the temporal correlation between remote neurophysiologi-
cal events; effective connectivity as the effect one neuronal
SPM and other software programmes can also be applied to region has on another. Functional connectivity, like all cor-
the study of local structural abnormalities in what is called relational methods, does not provide insight into how the
computational or voxel-based morphometry (VBM). Typically, observed results are mediated; a significant correlation simply
T1 structural images are spatially normalised in the same man- denotes some sort of interaction between regions. Effective
ner as functional images, and then partitioned or ‘segmented’ connectivity, in contrast, is closer to the intuitive notion
into grey and white matter and CSF using automated of a neuronal connection and depends on two models: an
template-based methods. A t-statistic can be calculated at anatomical model describing which (functionally segregated)
each voxel of two groups of normalised grey matter images regions are connected, and a mathematical model describing
and correction made for multiple testing as before. Note that how regions are connected (Friston 2002).
voxel-based methods detect changes in the surfaces or bound-
aries between different parts of the brain and any group differ- To illustrate the concept of effective connectivity, consider
ences are differences in the probability of, for example, grey Fig. 4.6. This shows a simplified diagram of the limbic basal
matter at a particular voxel. By contrast, ROI methods are ganglia thalamocortical loop (Alexander et al 1990). Using
used to detect changes in the volume of outlined structures. ROI methods, it is possible to determine brain activity for
Some advantages can therefore accrue from incorporating ROI each of the regions shown in Fig. 4.6. These values can then
methods into VBM – usually to focus the statistical analysis to be used to calculate an observed covariance matrix. Next, a
particular voxels of interest (see e.g. Job et al 2005) mathematical model of the connections shown in Fig. 4.6

83

Companion to Psychiatric Studies

AC and MOFC Volterra formulation. The influence on one brain region has
two components. First, there is a direct influence from a hier-
VS archically lower region (R1) on a higher region (R2). Second,
there is a modulatory influence from a super-ordinate brain
VP DMT region (R3) on the effects of R1 on R2. By introducing ‘moder-
Fig. 4.6 Limbic/basal ganglia/thalamocortical loop. AC, anterior ator’ variables, which reflect interaction between two regions
cingulate; MOFC, medial orbitofrontal cortex; VS, ventral striatum; producing activity in a third region, SEM can accommodate
VP, ventral pallidum; DMT, dorsal medial nucleus of thalamus. Volterra formulations.

Electrophysiological methods

can be defined using structural equation modelling (SEM) tech- Electroencephalography (EEG)
niques (also referred to as path analysis). A set of connection
strengths (path values, analogous to a regression coefficient) In conventional EEG, electrodes are placed on the scalp, which
between each region can thus be specified and compared with is a safe non-invasive procedure. Electrodes can also be placed
the observed matrix to determine any discrepancy. A different on the surface of the brain and within it using, for example,
set of connection strengths is then specified and the compari- transphenoidal routes. Scalp recording uses the International
son repeated. By systematically testing different connection 10–20 System of electrode placement to measure the summed
strengths until the discrepancy is minimised, an optimum set electrical activity of neurons discharging at the same time
can be defined which best fits the observed covariance matrix. (in phase), allowing detection of the well-known alpha, beta,
The influence of one neuronal system on another is thus esti- delta and theta rhythms. Evoked potentials (EP) represent
mated by the optimal set of path estimates. If one optimal much slower activity and average the EEG response to
set is obtained, e.g. from a group of depressed patients, and repeated sensory stimuli. Brain electrical activity mapping
another from a group of matched controls, then methods are (BEAM) is a method of forming images from EEG or EP data.
available to determine whether the sets are significantly differ-
ent. If so, this would indicate that one or more connections Magnetoencephalography (MEG)
differ between the depressed and non-depressed subjects.
The development of superconducting quantum interference
It should be noted that the anatomical model shown in devices in the 1980s allowed non-invasive measurement of the
Fig. 4.6 is necessarily simpler than that described previously small magnetic fields caused by neuronal discharge. Unlike EEG,
(Alexander et al 1990), because of the limited spatial resolu- MEG requires electrostatic shielding and head immobilisation.
tion of the imaging techniques. Even the highest resolution
brain imaging techniques tend to sample tens of thousands of The objective of EEG and MEG imaging is to identify
neurons per voxel. Consequently, sampling from one part of the locations of the sources of the electromagnetic activity.
the brain may produce quite different results from sampling This is done with software postulating the location of vari-
from another. These problems are examples of partial volume ous sources of activity and calculating a predicted pattern.
effects. Another pitfall of connectivity studies is that the ana- The prediction which best matches the observed pattern of
tomical model is not explicitly defined a priori, inflating the recorded EEG or MEG data defines the best estimate of neu-
risk of both false positives and difficulty in interpreting the ronal discharge. The main advantage of EEG and MEG techni-
results. In addition, the fact that functional imaging techniques ques is their excellent temporal resolution. MEG is an optimal
are unable to distinguish different neurophysiological events technique for detecting electromagnetic sources parallel to the
means that, for example, a high positive path value between scalp, while EEG is optimal for detecting perpendicular
two brain regions cannot be simply identified as ‘excitatory’, sources; pooling EEG and MEG data thus allows better source
or a negative value as ‘inhibitory’. Further, SEM cannot deal localisation. The main limitations of both EEG and MEG
with connections expressed in one context but not in another. imaging are relatively poor spatial resolution, particularly for
Such non-linearity of response is believed to occur in the brain, deep brain structures. There is, however, much interest in
and to take account of this ‘Volterra formulations’ can be used multimodal imaging to combine the advantages of, for example,
(Friston 2002). Figure 4.7 illustrates the concept of the EEG and fMRI.

R3 Neuroimaging studies of psychiatric
disorders

R1 R2 The literature on psychiatric imaging is now considerable and
many new studies are published each year. The main hypothe-
Fig. 4.7 Volterra formulation. Three brain regions: R1, R2 and R3. sis for the early work, partly limited by low spatial resolution,
R1 is lower in hierarchy than R2, the former ‘driving’ the latter. was that the major psychiatric disorders were biologically
R3, higher in hierarchy than other regions, modulates the influence based, and – that it might be possible to detect structural
of R1 on R2.

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Neuroimaging CHAPTER 4

and functional brain abnormalities in patients. There was often a 10-fold increase in the rate of ventricular dilatation in AD
little refinement of the prior hypothesis, such as where exactly patients of approximately 15% per year.
the abnormality might be found. Early studies particularly
implicated the prefrontal and temporal lobes in many These findings have been pursued with MRI studies. In
disorders. particular, voxel-based studies agree with postmortem data
that the disease process begins in and around the hippocam-
More recent studies implicate localised regions of these pus, with progressive atrophy in the medial temporal lobe
lobes but more specific replication at a subregional level is still and the temporoparietal cortex, and that the frontal lobes
required. Many studies are small, underlining the need for are usually only affected at a much more advanced stage (e.g.
meta-analyses, data pooling and multicentre studies. Another Scahill et al 2002). These measures do not, as yet, discriminate
general problem is that despite a great deal of imaging work different types of dementia or improve diagnostic precision
in normal humans and animals, we still have only a very over the careful application of clinical criteria. Recent studies
limited understanding of normal prefrontal and temporal func- have shown that hippocampal volumes can discriminate the
tion and functional segregation in particular. Such mapping is elderly with mild cognitive impairment from those without,
a necessary prelude to connectivity studies, yet psychopathol- and who will or will not progress to dementia (e.g. Thompson
ogy will at least in part reflect distributed structural and/or et al 2001). Novel techniques – such as ‘support vector
functional abnormality at a systems rather than localised level. machines’ – looking at all the information available in a sMRI
scan may be able to outperform such unidimensional analyses
Dementia (see e.g. Klo¨ppel et al 2008).

As the neurobiology of dementia has become clearer, the clin- Other dementias – structural and
ical differentiation of underlying aetiologies has become more spectroscopic abnormalities
complex. This is not just because of increasing recognition of
disorders other than Alzheimer’s disease and vascular demen- Discrimination between Alzheimer’s disease and vascular or
tia, but also because different pathophysiological processes multiinfarct dementia can often be made on the overall appear-
can have similar phenotypic expressions depending on the part ance of brain structure (Table 4.6). Dementia with Lewy bodies
of the brain affected. For example, Alzheimer’s disease typi- (DLB) is less distinct from both diagnoses on these measures
cally presents with a temporoparietal predominance, but can (McKeith 2002).
present as a frontotemporal dementia.
Automated analyses of MRI white-matter segments, and
Alzheimer’s disease – structural diffusion tensor imaging (DTI) of white-matter tracts, are able
abnormalities to assay the reductions in white-matter connectivity which
may underly age-related cognitive decline and could also
Despite the above, there are consistent findings in neuro- have a role in the early detection of Alzheimer’s dementia.
imaging of the different dementias, which often show reason- Structural MRI and DTI may also be able to detect early
ably strong correlations with neuropathology (especially in changes in Creutzfeldt–Jakob disease (CJD) and the location
Alzheimer’s) and clinical characteristics such as cognitive of gliotic epileptic foci.
impairment. There is a remarkably consistent association
between temporal lobe pathology and psychotic features. Spectroscopy, of both the phosphorous and proton varieties,
CT and structural MRI have a role in detecting the 5% or so suggests early alterations in decreasing phosphomonoester/
of demented patients with gross abnormalities (Burns 1990), increasing phosphodiester level and reduced N-acetylcholine/
and the 1–2% with treatable causes such as normal pressure increased myoinositol, respectively, that may be more sensitive
hydrocephalus and subdural haematomas. than MRI; but very similar patterns are evident in a range of
disorders, including epilepsy and CJD.
More sophisticated applications of these techniques may
soon have clinical utility in early diagnosis. Early CT studies Alzheimer’s disease – functional
were unable to discriminate dementia of Alzheimer type abnormalities
(DAT) from normal ageing, probably because of lack of sensitiv-
ity and difficulties in reliable imaging of the hippocampus. The The clinical potential of brain imaging in the differential
Oxford project to investigate memory and ageing (OPTIMA) diagnosis of dementia has been most studied with SPECT in
conducted longitudinal temporal lobe oriented CT scans at Alzheimer’s disease. Characteristic SPECT findings in AD
yearly intervals from 1988 and found that a simple calliper mea- are bilateral reductions in cerebral blood flow in the parietal
surement of the medial temporal lobe minimum width, at the and temporal lobe, with relative sparing of the frontal and
level of the brainstem, was substantially lower in subjects with occipital lobes at least in the early stages of the disease. In con-
pathologically confirmed Alzheimer’s disease (AD). Although trast, patients with depression (and Korsakov psychosis)
controls showed an estimated age-related decline of about 1% usually have more pronounced frontal deficit (Goodwin
of medial temporal lobe thickness each year, the sensitivity 1996). SPECT in multi-infarct dementia shows a variable
and specificity of the finding was 93% and 81%, respectively pattern depending on the location of infarcts, for which
(Smith & Jobst 1996). Initial longitudinal analyses also found SPECT may be more sensitive even than structural imaging
techniques.

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Table 4.6 Discriminating dementia with imaging

Investigation Alzheimer’s disease Vascular/multiinfarct dementia Dementia with Lewy bodies

CT/MRI Generalised atrophy (>5% progression/year), Multifocal infarcts (usually bilateral) Relative sparing of medial temporal lobes
particularly in medial temporal lobes initially and atrophy (<5% progression/year) in majority
Deep white- Moderate increase Extensive Moderate increase
matter lesions
on MRI Frequent Extensive Frequent

Periventricular Global reduction, especially posterior Extensive variable, multifocal deficits Global reduction, especially occipital.
lucencies on MRI parietotemporal Medial temporal lobes relatively
preserved
SPECT HMPAO
scan (blood flow)

HMPAO, hexamethyl propyleneamine oxime.

The OPTIMA study found that parietotemporal perfusion Although a meta-analysis of these studies found an associa-
below the 5th percentile for controls, together with a similar tion between lateral ventricular enlargement and cumulative
degree of abnormality on CT of the medial temporal lobe hospitalisation, this could not clarify cause or effect (Raz &
width, had a sensitivity of 83% and a specificity of 91% for Raz 1990). Moreover, ventricular enlargement presumably
Alzheimer’s disease (Smith & Jobst 1996). Recent studies reflects tissue loss in (several) neighbouring brain regions.
have shown that SPECT blood flow data, and perhaps espe-
cially voxel-based analyses of them, may be able to discrimi- The first MRI study in schizophrenia was published in
nate Alzheimer’s disease from healthy ageing and depression 1984, but it was several years before researchers took full
(Dougall et al 2004). PET and fMRI may be able to detect very advantage of the technique in measuring regional brain
early disease changes and to identify patients who will develop volumes. There are now well over 100 controlled MRI studies
dementia at an early stage. For example, excessive memory- of various regional volumes in schizophrenia, and although they
related activation of the hippocampus, parietal and frontal find a slightly different pattern of significant differences,
regions in subjects at high genetic risk (presumably compen- several systematic and quantitative analyses have confirmed
sating for some premorbid cognitive difficulties) may be pre- volume reductions of approximately 3% in the whole brain,
dictive of patients who will develop dementia over the next 5% in the frontal and temporal lobes and 5–10% in temporal
2 years (Bookheimer et al 2000). Blood flow changes in DLB subregions (Lawrie & Abukmeil 1998; Wright et al 2000).
are more prominent in posterior regions and dopamine ligand Neuropathological studies suggest it is neuropil rather than
studies are very promising in the diagnosis of DLB, because neurone numbers that are reduced (Harrison 1999).
such patients show a relatively low uptake in basal ganglia
regions (similar to that observed in Parkinson’s disease) As with CT, MRI studies have found similar abnormalities
(McKeith et al 2007). The increasing ability to use PET ligands in first-episode cases and no clear relation to treatment (with
to visualise plaques and tangles in the brain may change how the exception of antipsychotic-related enlargement of parts
dementia is diagnosed and treated (de Leon et al 2007). of the basal ganglia). There are, however, a number of well-
conducted studies that suggest there may be some progressive
Schizophrenia reduction in frontal and temporal lobe volumes in the early
years of the condition, before and after onset (Pantelis et al
Generalised structural abnormalities 2003; Job et al 2005), some further progression in at least
some chronic cases, and possibly some effects of antipsychotic
Demonstration of ventriculomegaly in schizophrenia by CT medications and/or cannabis (Lawrie et al 2004; Hulshoff Pol
(Johnstone et al 1976) was greeted with scepticism, but has & Kahn 2008).
been convincingly replicated many times over (Lewis 1991).
A number of studies also showed that a similar degree of Other structural imaging techniques have delivered com-
abnormality was present in first-episode cases (Lewis 1991), plementary findings. There is a consistent MR spectros-
in keeping with a developmental rather than a degenerative copy literature, which finds reduced concentrations of some
cause. However, CT studies of cerebral ‘atrophy’, and lateral phospholipids and N-acetylaspartate in frontal and temporal
and third ventricular enlargement, failed to find consistent lobes, although it is unclear whether this reflects structural
associations with aetiological factors or disease characteristics. or functional abnormalities (Steen et al 2005). Similarly, the
emerging technique of DTI suggests abnormalities in frontal
areas, perhaps specifically those that are part of white-matter
tracts connecting the frontal and temporal or parietal lobes,
although the variety of techniques employed in often small
studies has led to some controversy (Kanaan et al 2005).

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Localised structural abnormalities schizophrenia, but further studies – particularly of the parietal
subregions – are required (Shenton et al 2001). A few studies
Prefrontal cortex (PFC) suggest cerebellar abnormalities but these also require wider
replication (Lawrie et al 2004).
The volume of the PFC is reduced by about 5% in schizo-
phrenia (Lawrie & Abukmeil 1998; Wright et al 2000). Functional abnormalities
A few parcellation studies suggest particular reduction in orbi-
tomedial cortex and the anterior cingulate, with mixed reports Prefrontal cortex
on specific frontal gyri and the dorsolateral PFC. These find-
ings are, however, very much in keeping with a larger number The first widely replicated functional imaging finding in
of VBM studies (Glahn et al 2008). There are also some schizophrenia was that of ‘hypofrontality’, a relative under-
intriguing suggestions of morphological disturbances – of activation of specifically the dorsolateral prefrontal cortex,
altered gyral complexity and (para) cingulate sulcus continuity. particularly on cognitive activation (Weinberger et al 1986).
There is increasing evidence that some of these PFC reduc- Such studies could not, however, ensure that the patients
tions are related to genetic risk factors for schizophrenia (e.g. were doing the tasks, let alone doing them as well as the con-
McIntosh et al 2007). This could explain why so few consis- trols. Pacing the task, for example by asking subjects in the
tent clinical associations of PFC volumes have been found. scanner to produce a response every 5 seconds, tends to
remove hypofrontality (Frith et al 1995) and suggests, if any-
Temporal lobe thing, a ‘hyperfrontality’ while patients are able to do the task,
and a progressive loss of frontal activity as the task becomes
The overall volume reduction is similar to that for the PFC, more difficult and performance fails (Fletcher et al 1998).
with possibly greater decrements and asymmetry abnormal- The issue is further complicated by frequent suggestions
ities in parts of the superior temporal gyrus. Medial temporal of an association between negative symptoms and hypofrontal-
structures may be reduced in volume by as much as 10%, ity, genetic effects (e.g. McIntosh et al 2007) and possible
although such findings have not always been replicated in post- subregional effects (see the subsection on mood disorders,
mortem work (Harrison 1999). There is good evidence that below).
reduced hippocampal volumes are found in the healthy rela-
tives of patients (Lawrie et al 2001; Boos et al 2007) and that Temporal
these may be attributable to an interaction between genetic
risk and environmental factors such as obstetric complications Resting SPECT and PET studies tended to find, if anything, a
(Shenton et al 2001). Wider temporal lobe volume losses seem ‘hypertemporality’. Subsequent studies have shown, with
to be associated with psychotic symptoms (Shenton et al remarkable consistency, that increased activation of (frontal
2001; Pantelis et al 2003; Job et al 2005), and may progress and) temporal language areas is associated with auditory hallu-
during the later stages of the illness (Hulshoff Pol & Kahn cinations. This work has been replicated with sophisticated
2008), possibly related to genetic factors and alcohol or fMRI studies (Shergill et al 2000). Functional abnormalities
cannabis consumption. of medial structures are evident on memory processing in the
hippocampus (Achim & Lepage 2005) and emotion processing
Basal forebrain in the amygdala (Hall et al 2008).

There is an impressive degree of agreement between ROI and Other regions
postmortem studies that the thalamus, and the mediodorsal
nucleus in particular, is smaller in schizophrenia than one There are a number of reports of abnormal activations in
would expect from global tissue reductions. This also appears patients with schizophrenia even on simple sensory and motor
to be true of genetic high-risk populations. There are also tasks, which suggest a generalised difficulty in cerebral organi-
intriguing, albeit inconsistent, findings that the adhesio inter- sation. This is compatible with increasing reports of parietal
thalamica (or massa intermedia) is more frequently absent in lobe abnormalities and suggestions of abnormal frontostriatal
people with schizophrenia. This midline structure is formed and fronto-thalamo-cerebellar networks, which can in turn be
in the first trimester, and similar qualitative abnormalities — related to abnormalities in dopamine signalling (Murray et al
such as the increased prevalence of a cavum septum pellucidum 2008) and synaptic plasticity (Stephan et al 2006).
between the frontal horns of the lateral ventricles — suggest
early disruption of brain development (Shenton et al 2001). Disconnectivity

The basal ganglia, on the other hand, are increased in In keeping with these observations, and the work of Frith and
volume, and this appears to be the structural abnormality in colleagues in particular (Frith et al 1995), there is a slowly
schizophrenia that is most likely to be attributable to anti- accumulating literature directly implicating disconnectivity in
psychotic medication (Wright et al 2000; Glahn et al 2008). schizophrenia (Stephan et al 2006). The best evidence at pres-
ent is for reduced frontotemporal connectivity, which may be
Other regions related to auditory hallucinations in particular (Lawrie et al
2002), but widespread intra- and inter-regional disconnections
There are suggestions that the parietal lobes may be structur-
ally abnormal and the occipital lobes essentially normal in

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are likely. Moreover, there is strongly suggestive evidence that white-matter hyperintensities and a high prevalence of cavum
this may be modulated by dopaminergic neurotransmission septum pellucidum (Reiss et al 2000), although there may
(Fletcher et al 1996). also be specific ageing and genomic imprinting effects. As yet,
there is a rather limited and poorly replicated literature on sex
Ligand studies chromosome aneuploidies, but there are replicated reports of
parietal lobe reductions in Turner’s syndrome (Reiss et al 2000).
Although the literature is inconsistent, overviews of PET
ligand studies suggest an increase in dopamine D2 receptor It is tempting to speculate that the reports of cerebellar
numbers (Laruelle 1998). Further, amphetamine challenge hypoplasia in VCFS, fragile X and autism (see below) may be
studies and, in particular, studies using fluorodopa binding related to the withdrawn, hyposocial behaviour evident in
as an index of presynaptic dopaminergic activity (Meyer- these disorders, as compared with the hypersociality observed
Lindenberg et al 2002), almost unanimously indicate abnor- in people with Williams syndrome. However, it is impor-
mally high dopamine turnover and sensitivity in the disease. tant to note that such findings are not particularly consistent,
Studies with other ligands are rare. and the specific behaviours differ between conditions; e.g.
fragile X and autism.

Summary Idiopathic disorders

Imaging studies in schizophrenia have provided new insights Attention deficit hyperactivity disorder (ADHD) and autism
into the pathophysiology of schizophrenia. Abnormalities are have been relatively well studied. Structural imaging studies
likely to be partly genetic and partly related to the expression in ADHD have shown reduced global, cerebellar, prefrontal
of the phenotype. Functional imaging is making progress in and caudate volumes (Valera et al 2007). Functional imaging
identifying the neurobiological substrates of particular symp- studies suggest hypoperfusion, hypometabolism and abnormal
toms. However, structure/function/clinical relationships need responses to attention and executive tasks in the same regions
to be much more accurately determined – and distinguished in ADHD, and implicate frontostriatal systems in particular
from other disorders – before these techniques can have suffi- (Dickstein et al 2006).
cient sensitivity or specificity for clinical use.
There is an increasing interest in autism and Asperger’s
Learning disability disorder, which fairly consistently show increases in whole
brain, cerebral hemispheres, cerebellum and caudate nucleus
It is surprising that arguably one of the most ‘organic’ areas volume, as well as reduced corpus callosum area (Stanfield
of psychiatric practice has, until recently, been a relatively et al 2008), in striking contrast with ADHD and despite
neglected area for imaging researchers. There is now a rapidly notable comorbidity between the two. The increases in whole
increasing literature on specific disorders. Further, routine brain volume may occur in the years after birth. Functional
neuroimaging, with MRI preferred to CT, is now recom- imaging studies implicate the prefrontal lobes, amygdala and
mended in the evaluation of children with global developmen- cerebellum – and the connections between these regions – in a
tal delay, particularly if abnormalities are found on physical variety of cognitive and emotional processing and coordination
examination (Shevell et al 2003). tasks (Minshew & Williams 2007).

Mood disorders

Disorders of known aetiology The traditional belief in complete recovery between episodes
of depression or mania delayed interest in searching for struc-
Patients with Down syndrome have a generalised reduction in tural brain changes in patients with mood disorder. However,
brain volume, changes in sulcal/gyral morphology, and more there are a number of common episodic medical disorders
specific deficits of the amygdala and hippocampal formation caused by permanent structural abnormalities, such as some
that are likely to further change with the development of cases of epilepsy, the early stages of multiple sclerosis and
dementia (Krasuski et al 2002). Most studies of children and exercise-induced cardiac arrhythmia secondary to coronary
adults with fragile X syndrome show reductions in the volume artery disease. There is now substantial evidence for structural
of the cerebellar vermis, particularly lobules VI and VII, and abnormalities in the brains of patients with unipolar and bipolar
may fail to activate frontal and parietal cortex on working mood disorders (Ebmeier et al 2006).
memory tasks. The latter has been related to gene expression
(Reiss et al 2000; Kwon et al 2001). In contrast, subjects with Structural abnormality
Williams syndrome may have an enlarged cerebellum, volume
reductions in the parietal and occipital lobes, and reduced An early meta-analysis concluded that ventricular enlargement
cerebral curvature, when compared with age- and gender- and sulcal prominence were evident in unipolar and bipolar
matched controls (Reiss et al 2000). A series of structural mood disorder patients, with an effect size only slightly less
MRI studies in velocardiofacial syndrome (VCFS) have consis- than for patients with schizophrenia (Elkis et al 1995). Clear
tently identified whole brain volume reductions of approxi- evidence for reduced cerebral and cerebellar size has been
mately 10% with relative sparing of the frontal lobes, prominent

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Neuroimaging CHAPTER 4

reported. Signal hyperintensities, which are punctate lesions a maintaining factor for depression. For example, anterior cin-
with reduced myelination and neuropil and are best visualised gulotomy involves the placement of small bilateral lesions in
on T2 images, occur more frequently than expected in both the anterior cingulate under stereotactic guidance and the best
unipolar and bipolar disorder (Videbech 1997; Kempton et al clinical response is associated with more anterior lesions
2008). Late-onset unipolar patients in particular tend to have placed within the region reported to be abnormal most often
many lesions, mostly periventricularly but also in the thalamus, in imaging studies (Steele et al 2007b). Deep brain electrical
in deep white matter and basal ganglia. Intriguingly, deep stimulation studies targeting the bilateral subgenual anterior
white-matter hyperintensities may be more common in bipolar cingulate or nucleus accumbens are promising recent
disorder (BPD) but other replicated structural findings in BPD approaches, as such interventions are both reversible and allow
are rare (Kempton et al 2008). Amygdala volumes may be a double-blind placebo-controlled study design (Mayberg et al
increased and, if so, this may be related to early age at onset, 2005).
elevated mood status or medication effects.
Higher resting amygdala activity in unipolar and bipolar
Generalised reduction in prefrontal lobe volume in patients mood disorder patients, relative to controls, has been reported
with major depression (Videbech 1997) and specific reduc- and this has been shown to correlate with depression severity
tions in the grey matter of the subgenual anterior cingulate (Drevets 2000). Antidepressant treatment has been found to
(Drevets 2000) have been reported quite consistently. Post- reduce amygdala activity in animals and humans. Again, how-
mortem studies have found reduction in grey matter glia and ever, this is unlikely to be specific and a range of influences
neurons in the subgenual anterior cingulate and orbitofrontal probably bear upon amygdala activity. A recent meta-analysis
cortex (Drevets 2000). Most people also now accept that hip- found, for example, that genetic variation in the serotonin
pocampal volume or size measured by MRI is reduced in transporter gene-linked polymorphic region (5-HTTLPR)
patients with unipolar depressive disorder (Ebmeier et al may account for up to 10% of variance in amygdala activation
2006). None of these findings are, however, specific to (Munafo et al 2008).
depression and the clinical correlates are accordingly unclear.
Factors such as the duration of illness, repeated episodes of Anxiety disorders
illness, treatment resistance and abuse early in life may all
be important. Antidepressants appear to be able to reverse Several studies and reviews of post-traumatic stress disorder
these changes and blocking hippocampal neurogenesis by irra- (PTSD) have found evidence of decreased hippocampal vol-
diation can prevent the action of antidepressants in animal ume (Karl et al 2006), and this may be related to cortisol
behavioural models of depression (Ebmeier et al 2006). excess. Obsessive-compulsive disorder (OCD) has been con-
Episodic memory is one of the main aspects of cognitive func- sistently associated with structural abnormalities of the thala-
tioning to be impaired in depression and hippocampal atrophy mus, basal ganglia and orbitofrontal cortex in a number of
might be a causal factor, but the direction of causality studies (Rotge et al 2009). There are replicated accounts
is uncertain. of temporal lobe reduction in panic disorder (after Fontaine
et al 1990) but no structural abnormalities have been reported
Functional abnormalities in generalised anxiety or phobic disorders.

The findings of functional imaging studies of patients with Anxiety disorders may generally represent dysfunction in
mood disorder are inconsistent and almost all are of depressed brain regions implicated in healthy subjects experiencing
patients, as manic patients are typically unable to comply with anxiety or fear as a normal transient emotion. A meta-analysis
study protocols. of functional imaging studies in healthy subjects experiencing
emotion induction (Phan et al 2002) reported a strong associ-
A meta-analysis of prefrontal functional abnormalities in ation between amygdala activity and fear induction, particu-
depression (Steele et al 2007a) found the medial prefrontal larly when visual induction methods were used. Emotion
cortex to be the most frequently reported site of abnormality. induction methods involving memory tend to activate the
This region is also reported most active when healthy subjects anterior cingulate. A recent meta-analysis of emotional proces-
experience emotion. It is centred on Broadmans Area (BA) 32 sing in PTSD, social anxiety disorder and specific phobia
but extends subgenually into BA 25. Two further clusters of (Etkin & Wager, 2007) concluded that greater activity in the
reported loci tend to occur: one in the lateral orbitofrontal insula and amygdala is consistently reported, similar to that
region, which is also active when healthy subjects experience observed during fear conditioning in healthy subjects. By con-
emotion (BA 47), and the other in the dorsolateral region trast, only patients with PTSD showed hypoactivation in
(BA 46 and 9) which is associated with cognitive processing. the dorsal and rostral anterior cingulate cortices and the ven-
There are, however, no consistent findings of either functional tromedial prefrontal cortex, structures linked to the experi-
overactivity or underactivity in these regions (Steele et al ence and regulation of emotion, suggesting a mechanism for
2007a). the emotional dysregulation symptoms in PTSD that extend
beyond an exaggerated fear response (Etkin & Wager 2007).
Identification of medial prefrontal functional abnormality In OCD, overactivity of the orbitofrontal cortex has been
in major depression does little in itself to clarify whether reported several times, as has increased or decreased basal
the abnormality is a cause, or effect, of the illness. Recently, ganglia activity, and may also be present in the unaffected
however, evidence has been obtained from experimental treat- relatives of sufferers (Menzies et al 2008).
ment studies that abnormal medial prefrontal activity may be

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