Assessment of the muscarinic receptor subtypes involved in pilocarpine-induced seizures in mice.
We have used the pilocarpine-induced seizure model in mice and i.c.v. injection of subtype-specific receptor antagonists to investigate the muscarinic receptor subtype specificity of cholinergically-activated seizures. The rank order potencies of antagonists for inhibition of pilocarpine-induced seizures are atropine = telenzepine > 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP) > pirenzepine with ID50's of 8.6, 12.0, 29.9, and 83.0 nmol/mouse, respectively. The M3-specific antagonists hexahydrosila-difenidol and its p-fluoro analog showed no effect on pilocarpine-induced seizures. The M2-specific antagonists gallamine and methoctramine cause seizures in mice in the absence of a pilocarpine injection. These seizures could be inhibited by coinjection of methoctramine with the M1-specific antagonist, pirenzepine. These data suggest a role of muscarinic M1 receptors in mediating pilocarpine-induced seizures and a role of the muscarinic M2 receptors in modulating neuronal activity.
Department of Pharmacology, University of Pennsylvania, Philadelphia.
J A
JA
Maslanski
R
R
Powelt
C
C
Deirmengiant
J
J
Patelt
D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D010276:Parasympatholytics / Q000494:pharmacology*; D010862:Pilocarpine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*
D010276:Parasympatholytics; D010880:Piperidines; D011976:Receptors, Muscarinic; D010862:Pilocarpine; C046338:telenzepine; C058297:4-fluorohexahydrosiladifenidol; D010890:Pirenzepine; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; C046773:hexahydrosiladifenidol