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.