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Rapid Development of Dopaminergic Supersensitivity in Reserpine- Treated Rats Demonstrated with 14C-2-Deoxyglucose Autoradiography

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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 enhanced re- cated in the pathogenesis of levodopa-induced dyskinesias, sponsivenessto a neurotransmitter after the surgical or phar- the most common and limiting side effect in the drug treat- macological interruption of synaptic function. Dopaminergic ment of Parkinson’s disease, yet the mechanisms that me- denervation supersensitivity in the basal ganglia 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 efficacy of selective D, agonists of Parkinson’s disease(Marsden et al., 1982; Agid et al., 1987). to stimulate locomotion. In rats with chronic dopamine 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 Parkinsonism, as in patients with Parkinson’s glucose utilization (RCGU) in the substantia nigra pars re- disease,supersensitive motor responseshave been observed fol- ticulata (SNr) has provided a metabolic correlate to the lowing dopamine agonist 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 receptor stimulation change in 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 stimulants, in contrast to their minor tion with single doses of reserpine (5.0 mg/kg, i.p.) and a- motor stimulant effects in 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 agonists are 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 dopamine depletion, 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 dopamine receptor number. The that the physiological and biochemical changesthat occur weeks development of supersensitive responses within 6-l 2 hr of to months following dopamine depletion, 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 quinpirole 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-tyrosine (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-raclopride (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 butaclamol. 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 dopamine receptor
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