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Home , AMPT, Dopaminergic, Dopamine agonist

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

Rapid Development of Supersensitivity in - 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 enhanced re- cated in the pathogenesis of levodopa-induced , sponsivenessto a after the surgical or phar- the most common and limiting in the treat- macological interruption of synaptic function. Dopaminergic ment of Parkinson’s disease, yet the mechanisms that me- denervation supersensitivity in the basalganglia has been im- diate altered drug sensitivity remain poorly understood. In plicated in the pathogenesisof levodopa-induced dyskinesias, animal models, one key component of denervation super- the most common and limiting side effect in the drug treatment sensitivity is the enhanced of selective D, of Parkinson’sdisease (Marsden et al., 1982; Agid et al., 1987). to stimulate locomotion. In rats with chronic de- The mechanismsthat mediate altered drug sensitivity in pa- pletion induced by 6-hydroxydopamine nigral lesion, the in- tients with Parkinson’s diseaseremain poorly understood. In creased ability of D, agonists to stimulate regional cerebral animal models of , as in patients with Parkinson’s glucose utilization (RCGU) in the pars re- disease,supersensitive motor responseshave been observed fol- ticulata (SNr) has provided a metabolic correlate to the lowing dopamine administration. In rats with chronic heightened motor response. In this study, we used the stim- dopamine depletion, the behavioral effects of D, and D, do- ulation of RCGU in the SNr as a sensitive in viva assay of D, pamine stimulation changein two important ways as agonist effect to examine the time course of development synthesized by Waddington and O’Boyle (1989): (1) D, agonists of supersensitivity in rats following acute dopamine deple- become full locomotor , in contrast to their minor tion with single doses of reserpine (5.0 mg/kg, i.p.) and a- motor effectsin controls, and the responseis blocked methyl-ptyrosine (AMPT; 100 mg/kg, i.p.). The stimulatory only by D,, not D,, antagonists;and 2) the motor effects of D, effect of the D, agonist SKF 36393 (30 mg/kg) on RCGU in agonistsare enhanced and are no longer blocked by D, antag- the SNr was first enhanced 6 hr after reserpine/AMPT injec- onists. To summarize, in rats with chronic dopaminedepletion, tion and was maximally enhanced at 12-24 hr (relative 2- motor stimulation induced by both D, and D, agonistsis en- deoxyglucose uptake increased 32-51%; P < 0.05). The hanced (i.e., supersensitivity) and there is a lossof the normally response to SKF 36393 returned to control values 5 d after present “cross-antagonism” (i.e., partial lossof D,/D, functional reserpine/AMPT injection. The single reserpine/AMPT injec- linkage). These observations suggestthat an improved under- tions depleted striatal dopamine to l-2% of control values standing of denervation supersensitivity will require analysisof from 3-46 hr postinjection, whereas D, and D, dopamine this complex shift in D,/D, function. receptor densities were unchanged at 24 hr. These results The time course of the development of denervation super- suggest that the heightened efficacy of D, agonists to stim- sensitivity may have important implications for its underlying ulate RCGU, one index of dopaminergic denervation super- mechanism. For example, if supersensitivedrug responsesde- sensitivity, correlates temporally with dopamine depletion velop within 24 hr of dopamine depletion, this would suggest but not with upregulation of number. The that the physiological and biochemical changesthat occur weeks development of supersensitive responses within 6-l 2 hr of to months following dopaminedepletion, while perhapsofadap- dopamine depletion limits the potential mechanisms that tive significance,are not of critical importance in determining mediate this phenomenon to processes that occur within this drug sensitivity. Behavioral studieshave suggestedthat the nor- time frame. Extrapolation from these results suggests that mally present “cross-antagonism” is lost within 24 hr of acute intermittent dopamine depletion in patients with Parkinson’s dopamine depletion. Breeseand Mueller (1985) demonstrated disease during the “off” state could result in enhanced func- that, in contrast to controls, the D, antagonist SCH 23390 no tional sensitivity to subsequent agonist challenge and con- longer blocked locomotor stimulation induced by the D, agonist tribute to the disabling dyskinesias that often accompany in rats reserpinized 24 hr earlier. Studies of the time the “on” state. courseof development of supersensitivity are lessclear but have suggestedthat the motor-stimulating effects of D, agonistsare Received Dec. 27, 1991; reviewed Mar. 6, 1992; accepted Mar. 17, 1992. enhanced 24-48 hr after reserpine injection (Amt, 1985; Starr We thank Carolyn Hansen for statistical consultation and Dr. J. P. Bennett for et al., 1987). While reserpine-induced monoamine depletion assistance with the measurement of tissue dopamine concentrations. This work was supported by NIH Grants KOS-NSO1174 and POl-NS30024 and by the differs from selective dopaminergic cell loss,behavioral super- National Parkinson Foundation. sensitivity develops in a similarly rapid fashion (within 36-48 Correspondence should be addressed to Dr. Joel M. Trwman. Deoartment of Neurology, Box 394, University of Virginia Health Scienc& Center,-Charlottes- hr) after 6-hydroxydopamine (6-OHDA) nigral lesion (Neve et ville, VA 22908. al., 1982). In this study, we use the stimulation of regional Copyright 0 1992 Society for Neuroscience 0270-6474/92/122875-05%05.00/O cerebral glucoseutilization (RCGU) as a sensitive in vivo assay 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 course of development of dopaminergic supersensitivity. The microdensitometer. Data for glucose utilization were expressed as a ratio of gray matter heightened efficacy of D, agonists to stimulate locomotion in 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- In intact rats, D, agonists mildly increase RCGU in the sub- culated rates of glucose utilization expressed as pmol/ 100 gm/min and stantia nigra pars reticulata (SNr; up 20%; Trugman et al., 1990). accurately reflects changes induced by pharmacological and physiolog- In contrast, in rats with chronic dopamine depletion induced ical stimuli (Sharp et al., 1983; Geary and Wooten, 1987). The data are summarized as mean & SD and represent four to eight optical density by 6-OHDA lesion, D, agonists markedly increase RCGU in measurements per brain region per animal, with four to eight rats per the SNr (up lOO-200%; Trugman and Wooten, 1987). There- treatment group. The doscresponse data were analyzed using a least- fore, D, agonist metabolic effects are enhanced in rats with squares means analysis following a significant full two-way analysis of chronic dopamine depletion, providing a quantitative measure variance. The time course data were analyzed using a one-way analysis of variance followed by the Tukey studentized range test. We considered of denervation supersensitivity. To determine the time course differences significant at P i 0.05. of development of enhanced D, agonist responses,we studied Receptor autoradiography. Rats were injected with reserpine (5.0 mg/ the effects of the D, agonist SKF 38393 on RCGU in rats fol- kg, i.p., at time 0) and AMPT (100 mg/kg, i.p., at 23 hr) and killed by lowing acute dopamine depletion with reserpineand a-methyl- decapitation at 24 hr. The brains were processed for quantitative in p- (AMPT). The primary aim of the experiments was vitro receptor autoradiography as described (Trugman et al., 1986). Tis- sue sections were incubated with saturating concentrations of the D, to determine whether D, agonist-induced metabolic responses antagonist ‘H-SCH 23390 (2 nM, 87 Ci/mmol; New England Nuclear) are enhanced within 24 hr of acute dopamine depletion. Once or the D, antagonist ‘H- (6 nM, 63 Ci/mmol; New England this was demonstrated, further experiments sought to identify Nuclear); nonspecific binding was defined in the presence of 2 /IM (+)- the earliest time at which responsesare enhanced, the time at . The mean values of ligand bound (measured B,,J for the reserpine- and vehicle-treated groups were compared using an indepen- which responsesare maximally enhanced,and the time at which dent t test. responsesreturn to control levels following single dosesof re- Measurement of striatal dopamine concentration. Rats were injected serpine and AMPT. The experiments also sought to determine with reserpine and AMPT according to the protocols described above whether enhanced functional responsesare accompanied by a and killed from 3 hr to 25 d following injection. Striata were dissected changein dopaminereceptor number and whether they correlate and tissue dopamine concentrations were measured using HPLC with electrochemical detection (Broaddus and Bennett, 1990). temporally with striatal dopamine depletion. Results Materials and Methods The stimulatory effects of SKF 38393 on RCGU in the SNr Animal preparation and were enhanced 24 hr after reserpine/AMPT injection (Fig. 1). Relative 2-DG uptake in the SNr in response to SKF 38393 (10 All experiments were performed on male Sprague-Dawley rats weighing 250-300 gm. Central venous catheters were inserted under light halo- and 30 mg/kg) was higher in reserpine/AMPT-treated rats than thane anesthesia the day before reserpine injection. The rats were fasted in controls [ 10 mg/kg: 2.78 f 0.15 (*SD) vs 2.48 f 0.07, P = overnight prior to “‘C-2-deoxyghtcose (2-DC) administration. 0.005; 30 mg/kg: 3.29 + 0.24 vs 2.49 f 0.24, P = 0.00011. Resetnine (Sigma) was dissolved in 50 ~1 of glacial acetic acid and Relative 2-DG uptake in the in responseto SKF 38393 diluted with 10% propylene glycol; AMPT methyl ester HCl (Sigma) and (?)-SKF 38393 HCL (Research Biochemicals Inc., Natick, MA) was not higher in reserpine/AMPT-treated rats than in controls were dissolved in water. Drugs were injected in a volume of 110-2.0 (30 mg/kg: 3.27 f 0.27 vs 3.44 f 0.35, P = 0.36). ml/kg body weight. Drug doses are expressed in terms of the weights The stimulatory effects of SKF 38393 (30 mg/kg) on RCGU of their salts. in the SNr were first enhanced 6 hr after reserpine/AMPT in- jection and were maximally enhanced at 12-24 hr (relative 2- Experimental design and data analysis DG uptake increased 32-51%; Figs. 2, 3). Five days after re- 2-DC experiments. To determine whether D, agonist-induced RCGU serpine/AMPT injection, the responseto SKF 38393 did not effects are enhanced 24 hr after acute dopamine depletion, a dose- response study was performed. Rats were injected with reserpine (5.0 differ significantly from control values. The reserpine/AMPT mg/kg, i.p., at time 0) and AMPT (100 mg/kg, i.p., at 23 hr) followed injections resulted in a profound depletion of striatal dopamine by SKF 38393 (1.0-30.0 mg/kg, i.v., at 24 hr). The controls were rats that was of rapid onset and long duration. Striatal dopamine 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 13%, 25%, and 31% of control values at 5, 10, and 25 d, re- at 24 hr. To identifv the earliest time at which RCGU effects are en- spectively. Twenty-four hours after reserpine/AMPT injection, hanced and the time of maximal enhancement, SKF 38393 (30 mg/kg, D, and D, dopamine receptor densitiesin the striatum and SNr i.v.) was administered 3, 6, 12, 24, and 48 hr after reserpine (5.0 mgl did not differ from control values (Fig. 4). kg, i.p.) injection. For these time points, AMPT (100 mg/kg, i.p.) was administered 1 hr prior to SKF 38393 injection. To determine the time Behavioral responsesto drug administration were observed at which D, agonist-induced metabolic responses return to control val- but not quantified. Rats injected with reset-pine(5.0 mg/kg, i.p.) ues after acute dopamine depletion, rats were injected with SKF 38393 became cataleptic within 60-90 min, demonstrating akinesia (30 mg/kg, i.v.) 5, 10, and 25 d after injection of reserpine (5.0 mg/kg, and ptosis.Twenty-four hours after reserpine/AMPT, SKF 38393 i.p.) and AMPT (100 mg/kg, i.p., given 2 hr after reserpine). For each of these protocols, rats were injected intravenously with 14C- (10 and 30 mg/kg) dramatically reversed the catalepsy within 2-DG (8 &i/100 gm body weight in 0.3-0.4 ml saline; 55 mCi/mM; 60 set of intravenous administration; the rats opened their eyes, American Radiolabeled Chemicals Inc., St. Louis, MO) 2 min after SKF becamemobile, and demonstrated facial and body grooming, 38393 administration. Unrestrained rats were studied in 23 x 35 cm sniffing, and chewing. Catalepsy was similarly reversed when cages. The rats were killed with a 50 mg/ml intravenous bolus of sodium SKF 38393 was administered at the 6 and 12 hr time points. pentobarbital 45 min after the 14C-2-DG injection. The brains were rapidly removed and frozen in liquid Freon. Duplicate 20 pm coronal When SKF 38393 was injected 3 hr after reserpine/AMPT, the sections were taken every 100 pm, thaw mounted on coverslips, dried animals aroused for approximately 15-20 min and then re- on a 40°C warming tray, and exposed to Kodak SB-5 x-ray film for 5 turned to an akinetic state. The Journal of Neuroscience, July 1992, 12(7) 2877

dose-RCGU responsecurve for the D, agonist SKF 38393 is

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

4.5 1 55 IT r 0 2-DG Uptake * 4.0 0 Striatal dopamine H T

25 .-: E 20 :: 4 Figure 2. The metabolic response to SKP 38393 (30 m&kg) in the SNr and striatal dopamine concentration as a function of time after reserpine/AMPT injection. Values are means + SD for four to eight rats per treatment group. The asterisks indicate a difference (P < 0.05) from non-reserpine-treated rats injected with SKP 38393 (30 mg/kg, time 0). The error bars (SD) for dopa- 036 12 24 48 120 240 600 mine concentrations at 3-24 hr are less Time after Reserpine (hours) 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 dopamine depletion, the The present study underscoresthe need to searchfor biochem- presentstudy addsfunctional and anatomical specificity to prior ical and physiological changesthat correlate temporally with behavioral work. altered functional drug response. The demonstration of enhanced metabolic responsesto D, The results suggesta complex relationship between enhanced 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 enhanced 6 hr after reserpineinjection, yet (Young et al., 1986), synthetic (Vernier et al., 1988), striatal dopamine is markedly depleted by 3 hr, suggeststhat and dopamine receptor (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 thesechanges are primarily 12-24 hr suggeststhat duration of dopamine depletion is a adaptive responsesto dopamine loss or whether they are of determinant factor in the drug response,but the attenuated re- critical importance in the regulation of sensitivity to dopamine sponse at 48 hr (when dopamine levels are still profoundly receptor stimulation. Clearly, changesthat evolve over weeks depleted), compared to 12-24 hr, arguesagainst a tight corre- to months do not mediate the enhancedeffects of D, receptor lation between enhancedmetabolic responsesand the duration stimulation observed within 6-12 hr of dopamine depletion. of dopamine depletion. Perhaps a clearer relationship would emerge if RCGU responseswere correlated with extracellular levels of dopamine measured in viva using microdialysis. The 400 normalization of the D, agonist responseat the 5 d time point, ~controt when striatal dopamine was 13% of control level, suggeststhat mReserpine/AMPT T this modest degreeof recovery of dopaminergic function is suf- 350 -- T t T ficient to restore normosensitivity to D, stimulation. 7 We found that D, and D, dopamine receptor number were 2 300 -- unchanged 24 hr after reset-pineinjection, suggestingthat in- .; creasesin receptor density do not account for enhanced sensi- ? 250 -- tivity to dopamine agonistsin states of dopamine depletion. \ z The results support the findings of Breeseet al. (1987), who E = 200 -- found no change in the binding characteristics of D, and D, r L T antagonist ligands in 6-OHDA-lesioned rats with documented F 0 c behavioral supersensitivity to D, and D, agonists.Small dec- El 150 -- rements(approximately 1O-20%) in striatal D, receptor density .u z (Marshall et al., 1989) and mRNA levels (Gerfen et al., 1990) P 100 -- have been reported in rats with long-term dopamine depletion, :: but it remains unclear how these changescould mediate en- 50 -- hanced functional responsesto D, stimulation. Alternative hy- pothesesof denervation supersensitivity are needed. The data presentedhere suggesta model of denervation su- o- 01 D2 Dl D2 persensitivity based on neuronal interaction in the striatum. GABA-utilizing medium spiny neurons constitute > 90% of in- Striatum I SNr trinsic striatal neurons, are the major target of dopamine input, Figure 4. EffectI of reserpine/AMPT treatment on D, and D, receptor and are the primary striatal projecting neurons(Smith and Bo- densities. Binding values of 3H-SCH 23390 (D, antagonist, 2 nM) and lam, 1990). Evidence suggeststhat the majority of striatonigral ‘H-raclopride (D, antagonist, 6 nM) represent means + SD for three or four rats per treatment group. Binding did not differ in rats injected neurons expressthe D, receptor (Get-fen et al., 1990) and the with reserpine/AMPT 24 hr previously compared to vehicle-injected majority of striatopallidal neurons expressthe D, receptor (Le controls (P values ranged from 0.38 to 0.64). Moine et al., 1991); the percentageof striatal cells that express The Journal of Neuroscience, July 1992, 72(7) 2879 both D, and D, receptors is not known. We propose that neurons Geary WA, Wooten GF (1987) In vivo tracer studies of glucose me- expressing D, receptors and neurons expressing D, receptors are tabolism, cerebral blood flow, and synthesis in naloxone pre- cipitated morphine withdrawal. Neurochem Res 12:573-580. functionally linked, or coupled, through the actions of dopa- Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ mine. The anatomic basis for this linkage may be a dual inner- Jr, Sibley DR(1990) D, and D, dopamine receptor-regulated gene vation by midbrain dopamine neurons, local axon collaterals, expression of striatonigral and striatopallidal neurons. Science 250: or interneurons. The rapid shift in drug sensitivity following 1429-1432. reserpine/AMPT treatment suggests that dopamine depletion, Harrison MB, Wiley RG, Wooten GF (1990) Selective localization of striatal D, receptors to striatonigral neurons. Brain Res 528:3 17-322. per se, results in the breakdown of this functional linkage, in Kadekaro M, Crane AM, Sokoloff L (1985) Differential effects of elec- supersensitive responses to D, and D, stimulation, and in the trical stimulation of sciatic nerve on metabolic activity in spinal cord loss of “cross-antagonism” demonstrable in behavioral studies. and dorsal root ganglion in the rat. Proc Nat1 Acad Sci USA 82:60 1O- The mechanisms by which dopamine may couple distinct pop- 6013. Lc Moine C, Normand E, Bloch B (199 1) Phenotypical characteriza- ulations of striatal output neurons remain to be elucidated. tion of the rat striatal neurons expressing the D, dopamine receptor The demonstration of supersensitive metabolic responses to gene. Proc Nat1 Acad Sci USA 88:4205-4209. D, stimulation within 6 hr of dopamine depletion may have Marsden CD, Parkes JD, Quinn N (1982) Fluctuations of disability implications for the pathogenesis and treatment of clinical fluc- in Parkinson’s disease-clinical aspects. In: Movement disorders (Marsden CD, Fahn S, eds), pp 96-122. London: Butterworth. tuations in Parkinson’s disease. Many patients with advanced Marshall JF. Navarrete R. Jovce JN (1989) Decreased striatal D, Parkinson’s disease cycle from mobility (“on”) to immobility binding~density following mesotelencephalic 6-hydroxydopamine in: (“off ‘), with states in between, every 2-3 hr throughout the day, jections: an autoradiographic analysis. Brain Res 493:247-257. and it is likely that these cycles are associated with extremely Mitchell IJ, Crossman AR (1984) In defence of optical density ratios high and low striatal dopamine concentrations alternating over in 2-deoxyglucose autoradiography. Brain Res 298: 19 l-l 92. Mouradian MM, Heuser IJE, Baronti F, Chase TN (1990) Modifi- the course of hours. Therefore, these patients likely experience cation of central dopaminergic mechanisms by continuous levodopa acute intermittent dopamine depletion daily. Extrapolation from theravv for advanced Parkinson’s disease. Ann Neurol 27: 18-23. the results presented here suggests that this intermittent dopa- Neve a, Kozlowski MR, Marshall JF (1982) Plasticity of neostriatal mine depletion could result in enhanced functional sensitivity dopamine receptors after nigrostriatal injury: relationship to recovery of sensorimotor functions and behavioral supersensitivity. Brain Res to subsequent agonist challenge and perhaps contribute to the 24413344. disabling dyskinesias that often accompany the “on” state. One Sharp FR, KilduffTS, Bzorgchami S, Heller HC, Ryan AF (1983) The corollary of the present hypothesis is that continuous replace- relationship of local cerebral glucose utilization to optical density ment with dopamine, or concomitant D, and D, stimulation, ratios. Brain Res 263:97-103. should restore functional linkage and normosensitivity to a do- Smith AD, Bolam JP (1990) The neural network of the as revealed by the study of synaptic connections of identified neu- pamine-denervated system and ameliorate the severity of levo- rones. Trends Neurosci 13:259-265. dopa-induced dyskinesias while maintaining near-normal pa- Starr BS, Starr MS, Kilpatrick IC (1987) Behavioural role of dopamine tient mobility. Experimental (Winkler and Weiss, 1989) and D, receptors in the reserpine-treated mouse. Neuroscience 22:179- clinical (Mouradian et al., 1990) observations support this pos- 188. sibility. Trugman JM, Wooten GF (1987) Selective D, and D, dopamine ag- onists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions. J Neurosci 7: References 2927-2935. Agid Y, Javoy-Agid F, Ruberg M (1987) Biochemistry of neurotrans- Trugman JM, Geary WA, Wooten GF (1986) Localization of D-2 mitters in Parkinson’s disease. In: Movement disorders 2 (Marsden dopamine receptors to intrinsic striatal neurones by quantitative au- CD. Fahn S. eds). vv 166-230. London: Butterworth. toradiography. Nature 323:267-269. Amt J (1985) Behavioural stimulation is induced by separate dopa- Trugman JM, Arnold WS, Touchet N, Wooten GF (1989) D, dopa- mine D-l and D-2 receptor sites in reserpine-pretreated but not in mine agonist effects assessed in vivo with [I%]-2-deoxyglucose auto- normal rats. Eur J Pharmacol 113:79-88. radioaravhv. J Pharmacol Exv Ther 250: 1156-l 160. Breese GR, Mueller RA (1985) SCH-23390 antagonism of a D-2 Trugmrm JM; James CL, Woo& GF (1990) Regulation of basal gan- depends upon neurons. Eur J glia glucose utilization by the D, dopamine receptor. Sot Neurosci Pharmacol 113:109-l 14. Abstr 16:81. Breese GR, Duncan GE, Napier TC, Bondy SC, Iorio LC, Mueller RA Vernier P, Julien J-F, Rataboul P, Fourrier 0, Feuerstein C, Mallet J (1987) 6-Hydroxydopamine treatments enhance behavioral re- (1988) Similar time course changes in striatal levels of glutamic acid sponses to intracerebral microinjection of D,- and D,-dopamine ag- decarboxylase and proenkephalin mRNA following dopaminergic onists into nucleus accumbens and striatum without changing do- deafferentation in the rat. J Neurochem 5 1: 1375-l 380. pamine antagonist binding. J Pharmacol Exp Ther 240:167-176. Waddington JL, O’Boyle KM (1989) Drugs acting on brain dopamine Broaddus WC, Bennett JP Jr (1990) Postnatal development of striatal receptors: a conceptual re-evaluation five years after the first selective dopamine function. II. Effects of neonatal 6-hydroxydopamine treat- D-l antagonist. Pharmacol Ther 43: l-52. ments on D, and D, receptors, adenylate cyclase activity and presyn- Winkler JD, Weiss B (1989) Effect of continuous exposure to selective aptic dopamine function. Dev Brain Res 521273-277. D, and D, dopaminergic agonists on rotational behavior in super- Costa11 B, Naylor RJ (1973) On the mode of action of . sensitive mice. J Pharmacol Exv Ther 49:507-5 16. Eur J Pharmacol21:350-361. Young WS, Bonner TI, Brann MR (1986) Mesencephalic dopamine Fleming WW, Trendelenburg U (1961) The development of super- neurons regulate the expression of‘neuropeptide mRNAs inthe rat sensitivity to after pretreatment with reserpine. J forebrain. Proc Nat1 Acad Sci USA 83:9827-9831. Pharmacol Exp Ther 133:4 l-5 1.