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)
Burke
K
K
Department of Pharmacology, School of Pharmacy, London.
Chandler
C J
CJ
Starr
B S
BS
Starr
M S
MS
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D010617:Phenanthridines / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D019257:Quinpirole; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D013331:Strychnine / Q000494:pharmacology
D014150:Antipsychotic Agents; D001058:Apomorphine; D001552:Benzazepines; D004298:Dopamine; D015259:Dopamine Agents; D004873:Ergolines; D007211:Indoles; D010617:Phenanthridines; D010852:Picrotoxin; D010862:Pilocarpine; D019257:Quinpirole; D013331:Strychnine; C054531:CY 208-243