CHARACTERIZATION OF ENHANCED BEHAVIORAL-RESPONSES TO L-DOPA FOLLOWINGREPEATED ADMINISTRATION IN THE 6-HYDROXYDOPAMINE-LESIONED RAT MODEL OF PARKINSONS-DISEASE

Long-term treatment of Parkinson's disease with dopamine-replacing age nts such as L-3,4-dihydroxyphenylalanine (L-DOPA) is compromised by ma ny side-effects, most notably involuntary movements, L-DOPA-induced dy skinesia. Acute challenge with dopamine-replacing drugs elicits a rota tional response in the 6-hydroxydopamine (6-OHDA)-lesioned rat model o f Parkinson's disease. This rotation is contraversive to the lesion an d is considered to represent an antiparkinsonian effect. More recently , it has become clear that the rotational response shows plasticity an d that repeated L-DOPA or apomorphine therapy is accompanied by a mark ed enhancement in this response. In this study, we demonstrate that th e enhanced behavioral response to repeated dopamine-replacement therap y seen in the 6-OHDA-lesioned rat has pharmacological characteristics similar to L-DOPA-induced dyskinesia seen in MPTP-lesioned primates an d man. Thus, the magnitude and rate of development of the enhanced res ponse to L-DOPA treatment is related to both the number of doses and t he size of the dose of L-DOPA administered. In contrast, de novo admin istration of dopaminergic drugs that are associated with a lower incid ence of dyskinesia, e.g., bromocriptine or lisuride, does not lead to an enhanced behavioral response following repeated treatment. However, following a single ''priming'' administration of apomorphine, the rot ational response elicited by subsequent bromocriptine administrations is enhanced with repeated treatment. Once established, the enhanced be havioral response to repeated L-D OPA-administration (6.5 mg/kg, twice daily) can, like L-DOPA-induced dyskinesia in man and MPTP-treated mo nkeys, be selectively reduced by coadministration of L-DOPA with the a lpha(2)-adrenergic receptor antagonist yohimbine (10 mg/kg, -95%), the 5-HT uptake inhibitor 5-MDOT (2 mg/kg, -90%), or the beta-adrenergic receptor antagonist propranalol (10 mg/kg, -35%). While these rats do not exhibit symptoms of dyskinesia per se, this rodent model does exhi bit behaviors, the underlying mechanism of which is likely to be simil ar to that underlying L-DOPA-induced dyskinesia and may prove useful i n studying the molecular and cellular mechanisms of L-DOPA-induced dys kinesia in Parkinson's disease. (C) 1998 Academic Press.