In 24 h reserpine-treated akinetic mice, locomotion was induced by the D1-selective agonist SKF 38393 (30 mg/kg IP), or by the mixed D1/D2 agonists L-dopa (150 mg/kg IP, plus benserazide 100 mg/kg IP) and apomorphine (0.5 mg/kg SC). The non-competitive NMDA receptor antagonist MK 801 (0.01-1.6 mg/kg IP) did not induce motor activity by itself, but potentiated the motor responses to L-dopa and apomorphine at roughly 10-fold lower doses than those which facilitated D1 responding. These data cast doubt on the notion that glutamate antagonists enhance the antiparkinsonian efficacy of mixed D1/D2 agonists solely through a D1 receptor mechanism.
The non-competitive NMDA polyamine site antagonist, eliprodil, was examined for its effects on exploratory activity in non-habituated mice and for its antiakinetic potential in reserpine-treated mice. A low dose of eliprodil (5 mg/kg) weakly stimulated locomotion in naive animals, whilst higher doses depressed rearing (20-40 mg/kg) and grooming (40 mg/kg), consistent with a sedative action. At no dose did eliprodil cause ataxia. In 24 h reserpine-treated mice, eliprodil (10-40 mg/kg) reversed akinesia, but this effect was subject to considerable inter-animal variation and was not statistically significant. Eliprodil did not alter the motor recovery elicited by the dopamine D1 agonist SKF 38393, or the dopamine D2 agonist RU 24213, and suppressed the motor stimulation induced by L-DOPA. These results indicate that eliprodil displays a far lower propensity than many other NMDA receptor antagonists for disturbing posture and gait, but lacks the essential motor stimulant action required to make it a safe and effective antiparkinsonian agent, at least in the reserpine-treated mouse model of Parkinson's disease.
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