GABAergic systems modulate nicotinic receptor-mediated seizures in mice

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 alpha7*-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 alpha7*-selective antagonist methyllycaconitine. The alpha4beta2*-selective antagonist dihydro-beta-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 GABAA 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.