GABAergic Systems Modulate Nicotinic Receptor-Mediated Seizures in Mice
2003
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 α7 * -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 α7 * -selective
antagonist methyllycaconitine. The α4β2 * -selective
antagonist dihydro-β-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 [ 3 H]GABA release or between
potencies of the antagonists in producing seizures and antagonist inhibition
of nicotine-stimulated [ 3 H]GABA release. However, a robust
correlation was detected between potencies of the agonists in producing
seizures and the IC 50 values for inhibition of nicotine-stimulated
[ 3 H]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.
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