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Characterization of Enhanced Behavioral Responses tol-DOPA Following Repeated Administration in the 6-Hydroxydopamine-Lesioned Rat Model of Parkinson's Disease

1998; Elsevier BV; Volume: 151; Issue: 2 Linguagem: Inglês

10.1006/exnr.1998.6819

1090-2430

Brian Henry, Alan R. Crossman, Jonathan M. Brotchie,

Neurotransmitter Receptor Influence on Behavior

Long-term treatment of Parkinson's disease with dopamine-replacing agents such asl-3,4-dihydroxyphenylalanine (l-DOPA) is compromised by many side-effects, most notably involuntary movements,l-DOPA-induced dyskinesia. Acute challenge with dopamine-replacing drugs elicits a rotational response in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. This rotation is contraversive to the lesion and is considered to represent an antiparkinsonian effect. More recently, it has become clear that the rotational response shows plasticity and that repeatedl-DOPA or apomorphine therapy is accompanied by a marked enhancement in this response. In this study, we demonstrate that the enhanced behavioral response to repeated dopamine-replacement therapy seen in the 6-OHDA-lesioned rat has pharmacological characteristics similar tol-DOPA-induced dyskinesia seen in MPTP-lesioned primates and man. Thus, the magnitude and rate of development of the enhanced response tol-DOPA treatment is related to both the number of doses and the size of the dose ofl-DOPA administered. In contrast,de novoadministration of dopaminergic drugs that are associated with a lower incidence 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 rotational response elicited by subsequent bromocriptine administrations is enhanced with repeated treatment. Once established, the enhanced behavioral response to repeatedl-DOPA-administration (6.5 mg/kg, twice daily) can, likel-DOPA-induced dyskinesia in man and MPTP-treated monkeys, be selectively reduced by coadministration ofl-DOPA with the alpha2-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 exhibit behaviors, the underlying mechanism of which is likely to be similar to that underlyingl-DOPA-induced dyskinesia and may prove useful in studying the molecular and cellular mechanisms ofl-DOPA-induced dyskinesia in Parkinson's disease.