Rapid Development of Dopaminergic Supersensitivity in ...

The Journal of Neuroscience, July 1992, 12(7): 2875-2879

Rapid Development of Dopaminergic Supersensitivity in Reserpine-

treated Rats Demonstrated with 14C-2-Deoxyglucose
Autoradiography

Joel M. Trugman and Christina L. James
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

Dopaminergic denervation supersensitivity has been impli- Denervation supersensitivity refers to a state of enhancedre-
sponsivenessto a neurotransmitter after the surgical or phar-
cated in the pathogenesis of levodopa-induced dyskinesias, macological interruption of synaptic function. Dopaminergic
denervation supersensitivity in the basalganglia hasbeenim-
the most common and limiting side effect in the drug treat- plicated in the pathogenesisof levodopa-induced dyskinesias,
the most common and limiting sideeffect in the drug treatment
ment of Parkinson’s disease, yet the mechanisms that me- of Parkinson’sdisease(Marsden et al., 1982;Agid et al., 1987).
The mechanismsthat mediate altered drug sensitivity in pa-
diate altered drug sensitivity remain poorly understood. In tients with Parkinson’s diseaseremain poorly understood. In
animal modelsof Parkinsonism,asin patientswith Parkinson’s
animal models, one key component of denervation super- diseases, upersensitivemotor responseshave beenobservedfol-
lowing dopamine agonist administration. In rats with chronic
sensitivity is the enhanced efficacy of selective D, agonists dopamine depletion, the behavioral effects of D, and D, do-
pamine receptor stimulation changein two important ways as
to stimulate locomotion. In rats with chronic dopamine de- synthesizedby Waddington and O’Boyle (1989): (1) D, agonists
become full locomotor stimulants, in contrast to their minor
pletion induced by 6-hydroxydopamine nigral lesion, the in- motor stimulant effectsin controls, and the responseis blocked
only by D,, not D,, antagonists;and 2) the motor effectsof D,
creased ability of D, agonists to stimulate regional cerebral agonistsare enhancedand are no longer blocked by D, antag-
onists.To summarize,in rats with chronic dopaminedepletion,
glucose utilization (RCGU) in the substantia nigra pars re- motor stimulation induced by both D, and D, agonistsis en-
hanced(i.e., supersensitivity)and there is a lossof the normally
ticulata (SNr) has provided a metabolic correlate to the present“cross-antagonism”(i.e., partial lossof D,/D, functional
linkage). Theseobservations suggesthat an improved under-
heightened motor response. In this study, we used the stim- standingof denervation supersensitivity will require analysisof
this complex shift in D,/D, function.
ulation of RCGU in the SNr as a sensitive in viva assay of D,
The time course of the development of denervation super-
agonist effect to examine the time course of development sensitivity may have important implications for its underlying
mechanism.For example, if supersensitivedrug responsesde-
of supersensitivity in rats following acute dopamine deple- velop within 24 hr of dopamine depletion, this would suggest
that the physiologicalandbiochemicalchangesthat occurweeks
tion with single doses of reserpine (5.0 mg/kg, i.p.) and a- to monthsfollowing dopaminedepletion, while perhapsofadap-
tive significance,are not of critical importance in determining
methyl-ptyrosine (AMPT; 100 mg/kg, i.p.). The stimulatory drug sensitivity. Behavioral studieshave suggestedthat the nor-
mally present “cross-antagonism” is lost within 24 hr of acute
effect of the D, agonist SKF 36393 (30 mg/kg) on RCGU in dopamine depletion. Breeseand Mueller (1985) demonstrated
that, in contrast to controls, the D, antagonist SCH 23390 no
the SNr was first enhanced 6 hr after reserpine/AMPT injec- longerblocked locomotor stimulation inducedby the D, agonist
quinpirole in rats reserpinized 24 hr earlier. Studiesof the time
tion and was maximally enhanced at 12-24 hr (relative 2- courseof development of supersensitivity arelessclear but have
suggestedthat the motor-stimulating effectsof D, agonistsare
deoxyglucose uptake increased 32-51%; P < 0.05). The enhanced24-48 hr after reserpineinjection (Amt, 1985; Starr
et al., 1987). While reserpine-inducedmonoamine depletion
response to SKF 36393 returned to control values 5 d after differs from selectivedopaminergic cell loss,behavioral super-
sensitivity developsin a similarly rapid fashion (within 36-48
reserpine/AMPT injection. The single reserpine/AMPT injec- hr) after 6-hydroxydopamine (6-OHDA) nigral lesion(Neve et
al., 1982). In this study, we use the stimulation of regional
tions depleted striatal dopamine to l-2% of control values cerebralglucoseutilization (RCGU) asa sensitivein vivo assay

from 3-46 hr postinjection, whereas D, and D, dopamine

receptor densities were unchanged at 24 hr. These results

suggest that the heightened efficacy of D, agonists to stim-

ulate RCGU, one index of dopaminergic denervation super-

sensitivity, correlates temporally with dopamine depletion

but not with upregulation of dopamine receptor number. The

development of supersensitive responses within 6-l 2 hr of

dopamine depletion limits the potential mechanisms that

mediate this phenomenon to processes that occur within this

time frame. Extrapolation from these results suggests that

intermittent dopamine depletion in patients with Parkinson’s

disease during the “off” state could result in enhanced func-

tional sensitivity to subsequent agonist challenge and con-

tribute to the disabling dyskinesias that often accompany

the “on” state.

Received Dec. 27, 1991; reviewed Mar. 6, 1992; accepted Mar. 17, 1992.

We thank Carolyn Hansen for statistical consultation and Dr. J. P. Bennett for
assistance with the measurement of tissue dopamine concentrations. This work
was supported by NIH Grants KOS-NSO1174 and POl-NS30024 and by the
National Parkinson Foundation.

Correspondence should be addressed to Dr. Joel M. Trwman. Deoartment of
Neurology, Box 394, University of Virginia Health Scienc& Center,-Charlottes-
ville, VA 22908.

Copyright 0 1992 Society for Neuroscience 0270-6474/92/122875-05%05.00/O

2876 Trugman and James * Rapid Development of Dopaminergic Supersensitivity

of D, agonist effect (Trugman et al., 1989) to examine the time d. Film autoradiographs were analyzed with a Leitz variable aperture
microdensitometer.
course of development of dopaminergic supersensitivity. The
heightened efficacy of D, agonists to stimulate locomotion in Data for glucose utilization were expressed as a ratio of gray matter
to corpus callosum optical densities (relative 2-DG uptake; Mitchell
dopamine-depleted animals has a regional metabolic correlate. and Crossman, 1984). Relative 2-DG uptake is linearly related to cal-
culated rates of glucose utilization expressed as pmol/ 100 gm/min and
In intact rats, D, agonists mildly increase RCGU in the sub- accurately reflects changes induced by pharmacological and physiolog-
ical stimuli (Sharp et al., 1983; Geary and Wooten, 1987). The data are
stantia nigra pars reticulata (SNr; up 20%; Trugman et al., 1990). summarized as mean & SD and represent four to eight optical density
In contrast, in rats with chronic dopamine depletion induced measurements per brain region per animal, with four to eight rats per
treatment group. The doscresponse data were analyzed using a least-
by 6-OHDA lesion, D, agonists markedly increase RCGU in squares means analysis following a significant full two-way analysis of
variance. The time course data were analyzed using a one-way analysis
the SNr (up lOO-200%; Trugman and Wooten, 1987). There- of variance followed by the Tukey studentized range test. We considered
differences significant at P i 0.05.
fore, D, agonist metabolic effects are enhanced in rats with
chronic dopamine depletion, providing a quantitative measure Receptor autoradiography. Rats were injected with reserpine (5.0 mg/
kg, i.p., at time 0) and AMPT (100 mg/kg, i.p., at 23 hr) and killed by
of denervation supersensitivity. To determine the time course decapitation at 24 hr. The brains were processed for quantitative in
vitro receptor autoradiography as described (Trugman et al., 1986). Tis-
of development of enhancedD, agonist responsesw, e studied sue sections were incubated with saturating concentrations of the D,
the effects of the D, agonist SKF 38393 on RCGU in rats fol- antagonist ‘H-SCH 23390 (2 nM, 87 Ci/mmol; New England Nuclear)
or the D, antagonist ‘H-raclopride (6 nM, 63 Ci/mmol; New England
lowing acute dopamine depletion with reserpineand a-methyl- Nuclear); nonspecific binding was defined in the presence of 2 /IM (+)-
butaclamol. The mean values of ligand bound (measured B,,J for the
p-tyrosine (AMPT). The primary aim of the experiments was reserpine- and vehicle-treated groups were compared using an indepen-
to determine whether D, agonist-induced metabolic responses dent t test.

are enhancedwithin 24 hr of acute dopamine depletion. Once Measurement of striatal dopamine concentration. Rats were injected
this wasdemonstrated, further experiments sought to identify with reserpine and AMPT according to the protocols described above
and killed from 3 hr to 25 d following injection. Striata were dissected
the earliest time at which responsesare enhanced,the time at and tissue dopamine concentrations were measured using HPLC with
electrochemical detection (Broaddus and Bennett, 1990).
which responsesaremaximally enhanced,andthe time at which
Results
responsesreturn to control levels following singledosesof re-
serpineand AMPT. The experiments alsosoughtto determine The stimulatory effects of SKF 38393 on RCGU in the SNr

whether enhancedfunctional responsesare accompaniedby a were enhanced24 hr after reserpine/AMPT injection (Fig. 1).

changein dopaminereceptornumber andwhetherthey correlate Relative 2-DG uptake in the SNr in response to SKF 38393 (10
temporally with striatal dopamine depletion.
and 30 mg/kg) washigher in reserpine/AMPT-treated ratsthan
Materials and Methods in controls [ 10 mg/kg: 2.78 f 0.15 (*SD) vs 2.48 f 0.07, P =

Animal preparation and drugs 0.005; 30 mg/kg: 3.29 + 0.24 vs 2.49 f 0.24, P = 0.00011.

All experiments were performed on male Sprague-Dawley rats weighing Relative 2-DG uptake in the striatum in responseto SKF 38393
250-300 gm. Central venous catheters were inserted under light halo- wasnot higher in reserpine/AMPT-treated rats than in controls
thane anesthesia the day before reserpine injection. The rats were fasted
overnight prior to “‘C-2-deoxyghtcose (2-DC) administration. (30 mg/kg: 3.27 f 0.27 vs 3.44 f 0.35, P = 0.36).

Resetnine (Sigma) was dissolved in 50 ~1 of glacial acetic acid and The stimulatory effectsof SKF 38393 (30 mg/kg) on RCGU
diluted with 10% propylene glycol; AMPT methyl ester HCl (Sigma) in the SNr were first enhanced6 hr after reserpine/AMPT in-
and (?)-SKF 38393 HCL (Research Biochemicals Inc., Natick, MA)
were dissolved in water. Drugs were injected in a volume of 110-2.0 jection and were maximally enhanced at 12-24 hr (relative 2-
ml/kg body weight. Drug doses are expressed in terms of the weights
of their salts. DG uptake increased32-51%; Figs. 2, 3). Five days after re-

Experimental design and data analysis serpine/AMPT injection, the responseto SKF 38393 did not
differ significantly from control values. The reserpine/AMPT
2-DC experiments. To determine whether D, agonist-induced RCGU
effects are enhanced 24 hr after acute dopamine depletion, a dose- injections resultedin a profound depletion of striatal dopamine
response study was performed. Rats were injected with reserpine (5.0
mg/kg, i.p., at time 0) and AMPT (100 mg/kg, i.p., at 23 hr) followed that was of rapid onset and long duration. Striatal dopamine
by SKF 38393 (1.0-30.0 mg/kg, i.v., at 24 hr). The controls were rats
pretreated with vehicle followed by SKF 38393. The doses and timing was reduced to l-2% of control value [control, 48 f 5 (&SD)
of resernine and AMPT iniections were modified from a published
nrotocol (Breese and Mueller, 1985) in which it was demonstrated that pmol/mg tissue] from 348 hr postreserpineand recovered to
a similar drug treatment resulted in 98% depletion of striatal dopamine
at 24 hr. To identifv the earliest time at which RCGU effects are en- 13%, 25%, and 31% of control values at 5, 10, and 25 d, re-
hanced and the time of maximal enhancement, SKF 38393 (30 mg/kg, spectively. Twenty-four hours after reserpine/AMPT injection,
i.v.) was administered 3, 6, 12, 24, and 48 hr after reserpine (5.0 mgl
kg, i.p.) injection. For these time points, AMPT (100 mg/kg, i.p.) was D, and D, dopamine receptor densitiesin the striatum and SNr
administered 1 hr prior to SKF 38393 injection. To determine the time
at which D, agonist-induced metabolic responses return to control val- did not differ from control values (Fig. 4).
ues after acute dopamine depletion, rats were injected with SKF 38393 Behavioral responsesto drug administration were observed
(30 mg/kg, i.v.) 5, 10, and 25 d after injection of reserpine (5.0 mg/kg,
i.p.) and AMPT (100 mg/kg, i.p., given 2 hr after reserpine). but not quantified. Ratsinjected with reset-pine(5.0 mg/kg, i.p.)

For each of these protocols, rats were injected intravenously with 14C- becamecataleptic within 60-90 min, demonstrating akinesia
2-DG (8 &i/100 gm body weight in 0.3-0.4 ml saline; 55 mCi/mM; andptosis.Twenty-four hoursafter reserpine/AMPT, SKF 38393
American Radiolabeled Chemicals Inc., St. Louis, MO) 2 min after SKF
38393 administration. Unrestrained rats were studied in 23 x 35 cm (10 and 30 mg/kg) dramatically reversed the catalepsy within
cages. The rats were killed with a 50 mg/ml intravenous bolus of sodium 60 setof intravenous administration; the rats openedtheir eyes,
pentobarbital 45 min after the 14C-2-DG injection. The brains were
rapidly removed and frozen in liquid Freon. Duplicate 20 pm coronal becamemobile, and demonstrated facial and body grooming,
sections were taken every 100 pm, thaw mounted on coverslips, dried
on a 40°C warming tray, and exposed to Kodak SB-5 x-ray film for 5 sniffing, and chewing. Catalepsy was similarly reversed when

SKF 38393 wasadministered at the 6 and 12 hr time points.
When SKF 38393wasinjected 3 hr after reserpine/AMPT, the

animals aroused for approximately 15-20 min and then re-

turned to an akinetic state.

The Journal of Neuroscience, July 1992, 12(7) 2877

A VEHICLE CONTROL dose-RCGU responsecurve for the D, agonist SKF 38393 is
shifted to the left with an increasein maximal responsef,ulfilling
0 RESERPINE/AMPT PRETREATMENT *+ the criteria for denervation supersensitivity(Fig. 1;Fleming and
Trendelenburg, 1961). The metabolic effectsare first enhanced
T 6 hr after reserpine/AMPT injection, are maximally enhanced
at 12-24 hr, and return to control values by 5 d. The reserpine/
1.0 I I II I AMPT combination profoundly depletedstriatal dopaminefrom
I ,I 30 3-48 hr postinjection, whereasD, and D, dopamine receptor
0 10 20 densities were unchanged at 24 hr. These results suggestthat
the heightenedefficacy of D, agoniststo stimulate RCGU, one
SKF 38393 (mg/kg) index of dopaminergic denervation supersensitivity, correlates
temporally with dopaminedepletion and not with upregulation
Figure 1. Dose-response analysis of D, agonist-induced metabolic of dopamine receptor number.
effects in the SNr 24 hr after reserpine/AMPT injection. Relative 2-DG
uptake in response to SKP 38393 (10 and 30 mg/kg) was higher in The novel finding in this study is that D, agonist-induced
reserpine/AMPT-treated rats (circles) than in controls (triangles). Values metabolic responsesare enhancedwithin 6 hr of dopaminede-
are means ? SD for four to eight rats per treatment group. The asterisks pletion. We have confidence in this result becauseRCGU in-
indicate a difference (P < 0.05) from the vehicle control group treated creaseshave beenshownto provide a sensitiveand valid mea-
with the same dose of SKP 38393. The pluses indicate a difference from sureof D, agonisteffect and becausethe result is consistentwith
rats that received the same pretreatment (reserpine/AMPT or vehicle) prior behavioral studies.In rats with chronic dopamine deple-
followed by SKP 38393 vehicle (SKP 38393, 0 mg/kg). tion, D, agonistsdose-dependentlyincreaseRCGU in the SNr
and the responseis blocked by D, antagonists(Trugman and
Discussion Wooten, 1987;Trugman et al., 1989).The recentdemonstration
that striatonigral neuronsselectively expressD, receptors(Ger-
This study demonstratesthat D, agonist-inducedmetabolic re- fen et al., 1990; Harrison et al., 1990; Le Moine et al., 1991)
sponsesareenhancedwithin 24 hr of acutedopaminedepletion alongwith the recognition that RCGU reflectsprimarily activity
in rats. Twenty-four hours after reserpine/AMPT injection, the in nerve terminals (Kadekaro et al., 1985), supportsthe inter-
pretation that RCGU increasesin the SNr reflect a direct stim-
ulation of striatonigral neurons.The rapid development of do-
paminergicdenervation supersensitivity hasbeendemonstrated
previously usingbehavioral measuresof drug effect. Costa11and
Naylor (1973) showedthat the intensity and duration of apo-
morphine-induced stereotypedbehavior are enhancedwithin 6
hr of reserpineinjection; similarly, locomotor activity induced
by D, agonistsis potentiated 24-48 hr after reserpineinjection
(Arm, 1985; Starr et al., 1987). By suggestingthat D, receptor
stimulation resultsin increasedratesof glucoseutilization with-

4.5 1 0 2-DG Uptake r 55
0 Striatal dopamine
IT *
T
H4.0

036 12 24 48 120 240 25 .-: Figure 2. The metabolic response to
E SKP 38393 (30 m&kg) in the SNr and
striatal dopamine concentration as a
20 :: function of time after reserpine/AMPT
4 injection. Values are means + SD for
four to eight rats per treatment group.
600 The asterisks indicate a difference (P <
0.05) from non-reserpine-treated rats
Time after Reserpine (hours) injected with SKP 38393 (30 mg/kg,
time 0). The error bars (SD) for dopa-
mine concentrations at 3-24 hr are less
than the size of the data point.

2878 Trugman and James * Rapid Development of Dopaminergic Supersensitivity

Naive rat 6 hr. post-reserpine 12 hr. post-reserpine
SKF 38393 (30 mg/kg) SKF 38393 (30 mg/kg) SKF 38393 (30 mg/kg)

Figure 3. W-2-DC autoradiographs through the midbrain at the level of the SNr (arrow) illustrating glucose utilization in response to SKF 38393
(30 mg/kg) injection. Increased uptake of I%-2-DG in the SNr is observed in rats treated with reserpine/AMPT 6 or 12 hr earlier in comparison
to naive rats.

in striatonigral neuronswithin 6 hr of dopaminedepletion, the The presentstudy underscoresthe needto searchfor biochem-
presentstudy addsfunctional and anatomicalspecificity to prior ical and physiological changesthat correlate temporally with
behavioral work. altered functional drug response.

The demonstration of enhancedmetabolic responsesto D, The resultssuggesat complex relationship betweenenhanced
stimulation within 6 hr of dopamine depletion has important functional responsesto D, stimulation and the extent and du-
implications for the mechanismof denervation supersensitivity. ration of striatal dopamine depletion. The fact that metabolic
Altered neurotransmitter function, including changesin peptide responsesare first enhanced6 hr after reserpineinjection, yet
(Young et al., 1986), synthetic enzyme (Vernier et al., 1988), striatal dopamine is markedly depleted by 3 hr, suggeststhat
and dopaminereceptor (Gerfen et al., 1990)mRNA levels, has the processesthat mediate the altered functional responsere-
.beenextensively documentedin animalswith chronic dopamine quire approximately 4-6 hr to develop. The responsepeak at
depletion. One question is whether thesechangesare primarily 12-24 hr suggeststhat duration of dopamine depletion is a
adaptive responsesto dopamine lossor whether they are of determinant factor in the drug response,but the attenuated re-
critical importance in the regulation of sensitivity to dopamine sponseat 48 hr (when dopamine levels are still profoundly
receptor stimulation. Clearly, changesthat evolve over weeks depleted), compared to 12-24 hr, arguesagainsta tight corre-
to months do not mediate the enhancedeffectsof D, receptor lation betweenenhancedmetabolic responsesand the duration
stimulation observed within 6-12 hr of dopamine depletion. of dopamine depletion. Perhapsa clearer relationship would
emergeif RCGU responseswere correlated with extracellular
400 T levels of dopamine measuredin viva usingmicrodialysis. The
normalization of the D, agonistresponseat the 5 d time point,
T ~controtmReserpine/AMPT tT when striatal dopamine was 13%of control level, suggeststhat
this modestdegreeof recovery of dopaminergicfunction is suf-
350 -- ficient to restorenormosensitivity to D, stimulation.

7 IILr T We found that D, and D, dopamine receptor number were
2 300 -- unchanged24 hr after reset-pineinjection, suggestingthat in-
.; creasesin receptor density do not account for enhancedsensi-
tivity to dopamine agonistsin statesof dopamine depletion.
? 250 -- The results support the findings of Breeseet al. (1987), who
\ found no changein the binding characteristics of D, and D,
z antagonistligandsin 6-OHDA-lesioned rats with documented
E behavioral supersensitivity to D, and D, agonists.Small dec-
= 200 -- rements(approximately 1O-20%)in striatal D, receptor density
(Marshall et al., 1989)and mRNA levels (Gerfen et al., 1990)
F have beenreported in rats with long-term dopaminedepletion,
E0cl 150 -- but it remains unclear how these changescould mediate en-
hancedfunctional responsesto D, stimulation. Alternative hy-
.u pothesesof denervation supersensitivity are needed.
z
P 100 -- The data presentedhere suggesta model of denervation su-
:: persensitivity basedon neuronal interaction in the striatum.
GABA-utilizing medium spiny neuronsconstitute > 90% of in-
50 -- trinsic striatal neurons,are the major target of dopamineinput,
and are the primary striatal projecting neurons(Smith and Bo-
o- D2 Dl D2 lam, 1990).Evidence suggeststhat the majority of striatonigral
01 SNr neurons expressthe D, receptor (Get-fen et al., 1990) and the
majority of striatopallidal neuronsexpressthe D, receptor (Le
Striatum Moine et al., 1991); the percentageof striatal cellsthat express

Figure 4. Effect of reserpine/AMPT treatment on D, and D, receptor
densities. Binding values of 3H-SCH 23390 (D, antagonist, 2 nM) and
‘H-raclopride (D, antagonist, 6 nM) represent means + SD for three or
four rats per treatment group. Binding did not differ in rats injected
with reserpine/AMPT 24 hr previously compared to vehicle-injected
controls (P values ranged from 0.38 to 0.64).

The Journal of Neuroscience, July 1992, 72(7) 2879

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