Effects of dopamine D1 and D2 receptor agonists and antagonists on seizures induced by chemoconvulsants in mice.

Abstract

Dopamine agonists and antagonists with different affinities for D1 and D2 receptors in the brain were assessed for their ability to affect clonic seizures in mice induced by chemoconvulsants. The dopamine D2 antagonists remoxipride (5-20 mg/kg) and raclopride (5-20 mg/kg), haloperidol (2.5 and 5 mg/kg) and the D1 antagonist SCH 23390 (0.3, 1.5 mg/kg) did not markedly modify seizures induced by pentylenetetrazole, picrotoxin or bicuculline. The dopamine D2 agonist quinpirole only weakly blocked the action of pentylenetetrazole while the D1 agonist SKF 38393 (1-10 mg/kg subcutaneously) caused a dose-dependent blockade of pentylenetetrazole-induced seizures. The D1/D2 agonist apomorphine given at "postsynaptic" doses (1 and 2 mg/kg) blocked pentylenetetrazole-induced seizures. The protection afforded by apomorphine against pentylenetetrazole seizures appeared to be associated with its activation of both D1 and D2 receptors since both raclopride and SCH 23390 blocked the action of apomorphine. Reserpine and the two partial dopamine autoreceptor agonists, (-)3-PPP and HW-165, at high (non-autoreceptor selective) doses induced seizures in animals treated with the subconvulsive dose of pentylenetetrazole. The overall results suggest that dopamine receptor blockade has a minor or limited effect on seizures caused by GABA inhibition. The anticonvulsant effect of dopamine agonists such as apomorphine appears to be mediated by postsynaptic dopamine D1 and D2 receptors. Stimulation of dopamine D1 receptors can reduce seizure activity caused by GABA receptor blockade possibly by facilitation of GABA transmission in the striatum and substantia nigra.