Pharmacological characterization of nicotine-induced seizures in mice

Pharmacological mechanisms involved in nicotine-induced seizures were investigated in mice by testing the ability of several nicotinic agonists in producing seizures after peripheral administration. In addition, nicotinic antagonists such as hexamethonium, mecamylamine, dihydro-beta-erythroidine, and methyllycaconitine citrate (MLA) were used in combination with nicotine. We also examined the involvement of calcium channels, N-methyl-D-aspartate receptors, and nitric oxide formation in nicotine-induced seizures. Our results showed that the peripheral administration of nicotine produced seizures in a stereospecific and mecamylamine-sensitive manner. Nicotine-induced seizures are centrally mediated and involve the activation of alpha7 along with other nicotinic receptor subunits. Indeed, MLA, an alpha7-antagonist, blocked the effects of nicotine after peripheral and central administration. The extent of alpha4beta2-receptor subtype involvement in nicotine-induced seizures was difficult to assess. On one hand, we observed that dihydro-beta-erythroidine (a competitive antagonist) failed to block the effects of nicotine. In addition, a poor correlation was found between binding affinity for (3)H-nicotine-labeled sites (predominantly alpha4beta2) and seizures potency for several nicotinic agonists. On the other hand, mecamylamine, a noncompetitive antagonist, blocked nicotine-induced seizures more potently than MLA. Furthermore, its potency in blocking seizures was in the same general dose range of other nicotinic effects that are not alpha7 mediated. These results suggest that this receptor subtype does not play a major role in nicotine-induced seizures. Our findings also suggest that nicotine enhances the release of glutamate either directly or indirectly (membrane depolarization that opens L-type calcium channels). Glutamate release in turn stimulates N-methyl-D-aspartate receptors, thus triggering the cascade of events leading to nitric oxide formation and possibly seizure production.