Seizure promotion by D1 agonists does not correlate with other dopaminergic properties.
A range of D1 receptor agonists were tested for their ability to facilitate limbic motor seizures induced by a subthreshold dose of the chemoconvulsant pilocarpine (100 mg/kg IP) in mice. ED50 values (mumol/kg) were calculated from log dose-probit analyses, giving relative proconvulsant potencies of SKF 82958 > CY 208-243 > SKF 77434 = SKF 75670 = SKF 80723 > SKF 38393. The compound SKF 82526, which poorly crosses the blood-brain barrier, did not lower the seizure threshold. Convulsions consisted of rearing and forepaw myoclonus, leading to status epilepticus at higher doses of the D1 agonists. No deaths were recorded. A maximum seizure incidence of 50% was obtained with SKF 75670, compared to 100% for the other compounds. Apart from SKF 82526, the D1 agonists all elicited behavioural signs of central D1 receptor stimulation, including motor restlessness, grooming and sniffing. There was no obvious relationship between the abilities of these D1 agonist drugs to promote epilepsy and their effects on unconditioned motor behaviour, or their affinities and efficacies at the striatal D1 receptor. It is concluded that a reduction of the seizure threshold is an inevitable consequence of central D1 receptor stimulation with existing D1 agonists.
Starr
M S
MS
Department of Pharmacology, School of Pharmacy, London, United Kingdom.
Starr
B S
BS
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D008032:Limbic System / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019832:N-Methylscopolamine; D010276:Parasympatholytics / Q000008:administration & dosage / Q000494:pharmacology; D010862:Pilocarpine; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced*
D015259:Dopamine Agents; D010276:Parasympatholytics; D017447:Receptors, Dopamine D1; D012602:Scopolamine Derivatives; D010862:Pilocarpine; D000262:Adenylyl Cyclases; D019832:N-Methylscopolamine