Received for publication April 14, 2003.
Revised May 5, 2003.
Accepted for publication June 10, 2003.

GABAergic systems modulate nicotinic receptor-mediated seizures in mice

Abstract

The pharmacology of nicotinic receptor-mediated seizures was investigated in C3H mice. Eleven nicotinic agonists and six antagonists were administered centrally (icv). Epibatidine and epiboxidine were the most potent agonists tested, while ACh and the 7*-selective compounds, 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, MLA. The 42*- selective antagonist, DHE, 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 excitatory amino acid receptor agonist, kainate. Based on these findings, we present a model for nicotinic receptor-mediated seizures mediated through GABAergic systems.

Key words: GABA, acetylcholine, epibatidine, nicotine, nicotinic receptors, seizures

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