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BEHAVIORAL PHARMACOLOGY

GABAergic Systems Modulate Nicotinic Receptor-Mediated Seizures in Mice

Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado (P.D.); and Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (S.H., Y.L., A.C.C.)

The pharmacology of nicotinic receptor-mediated seizures was investigated in C3H mice. Eleven nicotinic agonists and six antagonists were administered centrally (i.c.v.). Epibatidine and epiboxidine were the most potent agonists tested, whereas acetylcholine and the 7^*-selective compounds 3-(2,4-dimethoxybenzylidene)-anabaseine (GTS-21) and anabasine, were the least potent. Nicotine-induced seizures were blocked by cotreatment with either the nonselective antagonist mecamylamine or the 7^*-selective antagonist methyllycaconitine. The 42^*-selective antagonist dihydro--erythroidine was ineffective at blocking seizures. However, high doses of all six antagonists tested were fully efficacious in producing seizures, with d-tubocurarine being the most potent and mecamylamine the least potent. Potential relationships between nicotinic receptor-mediated seizures and drug effects on GABA function were also investigated. No correlation was seen between potencies of the agonists in producing seizures and stimulating [³H]GABA release or between potencies of the antagonists in producing seizures and antagonist inhibition of nicotine-stimulated [³H]GABA release. However, a robust correlation was detected between potencies of the agonists in producing seizures and the IC₅₀ values for inhibition of nicotine-stimulated [³H]GABA release produced by agonist-induced receptor desensitization. We also compared inbred mouse strain sensitivity to nicotine, picrotoxin, bicuculline, and kainate-induced seizures. Robust positive correlations were revealed for nicotine-induced seizures and seizures induced by either picrotoxin or bicuculline, both GABA_A receptor antagonists. No correlation was found between nicotine-induced seizures and those induced by the excitatory amino acid receptor agonist kainate. Based on these findings, we present a model for nicotinic receptor-mediated seizures mediated through GABAergic systems.

Address correspondence to: Dr. Allan C. Collins, Institute for Behavioral Genetics, University of Colorado/Boulder, 447 UCB, Boulder, CO 80309-0447. E-mail: al.collins{at}colorado.edu

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