Pertussis toxin potentiates seizures induced by pilocarpine, kainic acid and N-methyl-D-aspartate.
Previous studies with lithium have shown that it potentiated the in vivo response to cholinomimetics in rats, resulting in seizures at otherwise non-convulsant doses, but did not affect seizure activity induced by a number of chemical convulsants including kainic acid and N-methyl-D-aspartate (NMDA). In vitro experiments have suggested that lithium interferes with receptor-mediated second messenger production, possibly due to an action at G-proteins. The present study tested the hypothesis that selective inhibition of G-proteins by in vivo administration of pertussis toxin would induce effects similar to those of lithium. The results reported here demonstrate that pertussis toxin mimics lithium in potentiating the convulsant response to pilocarpine in rats. The effect of pertussis toxin was dose-dependent and the extent of potentiation was over 13-fold, which was remarkably similar to lithium. The seizures were prevented by pretreatment with atropine, phenobarbital or diazepam. L-Phenylisopropyladenosine (L-PIA) and MK-801 also demonstrated anticonvulsant activity, with MK-801 also protecting the rats against the rapid death associated with pertussis toxin/pilocarpine-induced seizures. Thus, seizures were cholinergically initiated and were controlled by the same drugs as were lithium/pilocarpine-induced seizures. The results illustrate that in several respects the response to cholinomimetics is modified in a similar manner by lithium and pertussis toxin. However, pertussis toxin lacks the specificity of lithium as it also potentiated the convulsant effects of kainic acid and NMDA.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham 35294.
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Ormandy
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Jope
D000244:Adenosine Diphosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology; D007276:Injections, Intraventricular; D007608:Kainic Acid; D008094:Lithium / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate; D037342:Pertussis Toxin; D010862:Pilocarpine; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced*; D013238:Stereotaxic Techniques; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D003292:Convulsants; D010566:Virulence Factors, Bordetella; D010862:Pilocarpine; D000244:Adenosine Diphosphate; D016202:N-Methylaspartate; D008094:Lithium; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007608:Kainic Acid