Treatment of Parkinson's disease with L-dopa therapy leads to long-term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine A2A receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor disability in MPTP-treated common marmosets in a dose-dependent manner. However, KW-6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW-6002 induced little or no dyskinesia in MPTP-treated primates previously primed to exhibit dyskinesia by prior exposure to L-dopa. These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.
The potent and long acting D-1 receptor agonist, A-77636 reverses motor deficits in MPTP treated common marmosets following subcutaneous or oral administration. We now explore the effects of acute versus repeated administration of A-77636 and the relative roles of D-1 and D-2 receptor involvement in its antiparkinsonian actions. Acute oral administration (0.18-9.0 mg/kg) or subcutaneous administration (0.036-1.08 mg/kg) of A-77636 produced well co-ordinated bouts of discontinuous locomotor activity. There was no evidence of repetitive or stereotyped movements. However, oral administration of A-77636 (1.44 mg/kg) on alternate days for 10 days produced tolerance to the increase in locomotor activity and improvement of disability. Pretreatment with the D-1 antagonist SCH 23390 (0.625, 2.5 or 5.0 mg/kg, intraperitoneally), produced a dose dependent reduction in locomotor activity and antagonised the reduction in disability scores following administration of A-77636 (0.36 mg/kg, subcutaneously). The inhibitory effects of SCH 23390 lasted for some 2-5 hours after which the activity of A-77636 was gradually restored. Unexpectedly, pretreatment with the D-2 antagonist raclopride (1.25, 5.0 or 20.0 mg/kg, intraperitoneally), dramatically diminished the antiparkinsonian effects of A-77636 (0.36 mg/kg, subcutaneously) in a dose dependent manner. The dependence of the antiparkinsonian activity of A-77636 on intact D-2 receptor function, suggests a need for endogenous D-2 receptor tone to express D-1 mediated locomotor activity.
Dyskinesias occur in the majority of patients with Parkinson's disease chronically treated with L-DOPA and also occur in several nonhuman primate species after 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) and L-DOPA treatment. The common marmoset (Callithrix jacchus) shows parkinsonian motor deficits after MPTP administration, and we now report dyskinesias occurring in this species during chronic L-DOPA exposure. Marmosets rendered chronically parkinsonian after MPTP administration were treated orally with L-DOPA plus carbidopa for 3 weeks. After several days the animals began to display chorea, choreoathetosis, and dystonia. The severity of dyskinesias varied between the animals, with the most severely parkinsonian animals displaying the most dyskinetic movements. Each animal showed an idiosyncratic pattern of dyskinesias, which was highly reproducible. These L-DOPA-primed animals also received other D2 D1, and mixed D1/D2 agonist drugs. Quinpirole, bromocriptine, pergolide, apomorphine, and A-77636 all produce dyskinesias that were identical in character to those seen after L-DOPA administration, but the D1 agonist A-77636 gradually abolished dyskinesias while preserving its antiparkinsonian activity. The MPTP-treated marmoset provides a useful model in which to study dyskinesias in Parkinson's disease and to examine new therapeutic strategies aimed at alleviating this common side effect of chronic dopamine replacement therapy.
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