Seizure promotion and protection by D-1 and D-2 dopaminergic drugs in the mouse

Mice injected with pilocarpine (100-400 mg/kg plus 1 mg/kg methylscopolamine), picrotoxin (0.75-6 mg/kg) or strychnine (0.75-6 mg/kg) exhibited clonic or clonic/tonic convulsions. Pretreatment with the D-1 agonist CY 208-243 (0.375-1.5 mg/kg) dose-dependently potentiated the convulsions elicited by 100 mg/kg pilocarpine, but had neither a convulsant nor anticonvulsant effect in mice receiving picrotoxin (3 or 6 mg/kg) or strychnine (0.75 or 1.5 mg/kg). This facilitatory effect of CY 208-243 was abolished by the D-1 antagonist SCH 23390 (0.2 mg/kg). SCH 23390 by itself (0.05-0.8 mg/kg) dose-dependently protected mice against pilocarpine (400 mg/kg) seizures. Stimulating D-2 receptors with LY 171555 (0.167-4.5 mg/kg) dose-dependently protected mice against seizure activity induced by pilocarpine, but neither protected nor sensitised mice given picrotoxin or strychnine. The neuroleptics haloperidol (1-4 mg/kg), sulpiride (10-50 mg/kg), metoclopramide (1.25-6.25 mg/kg), thioridazine (0.5-2 mg/kg) and clozapine (0.5-2 mg/kg) had no effect on the seizure threshold to 100 mg/kg pilocarpine by themselves, although 10 mg/kg thioridazine and clozapine caused 100% convulsions, possibly through a toxic action. When administered in conjunction with a minimally effective quantity of CY 208-243 (0.375 mg/kg), however, all five neuroleptics interacted synergistically with the D-1 agonist to promote convulsions to pilocarpine (100 mg/kg). No such interaction occurred between submaximally protective doses of the D-1 blocker SCH 23390 (0.05 and 0.2 mg/kg) and a wide range of doses of the D-2 stimulant LY 171555 (0.167-4.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)