Pharmacological characterization of nicotine-induced seizures in mice

Pharmacological mechanisms involved in nicotine-induced seizures were inves tigated in mice by testing the ability of several nicotinic agonists in pro ducing seizures after peripheral administration. In addition, nicotinic ant agonists such as hexamethonium, mecamylamine, dihydro-beta-erythroidine, an d 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 res ults showed that the peripheral administration of nicotine produced seizure s in a stereospecific and mecamylamine-sensitive manner. Nicotine-induced s eizures are centrally mediated and involve the activation of alpha 7 along with other nicotinic receptor subunits. Indeed, MLA, an alpha 7-antagonist, blocked the effects of nicotine after peripheral and central administratio n. The extent of alpha 4 beta 2-receptor subtype involvement in nicotine- i nduced seizures was difficult to assess. On one hand, we observed that dihy dro-beta-erythroidine (a competitive antagonist) failed to block the effect s of nicotine. In addition, a poor correlation was found between binding af finity for H-3-nicotine-labeled sites (predominantly alpha 4 beta 2) and se izures potency for several nicotinic agonists. On the other hand, mecamylam ine, a noncompetitive antagonist, blocked nicotine-induced seizures more po tently than MLA. Furthermore, its potency in blocking seizures was in the s ame general dose range of other nicotinic effects that are not alpha 7 medi ated. These results suggest that this receptor subtype does not play a majo r role in nicotine-induced seizures. Our findings also suggest that nicotin e enhances the release of glutamate either directly or indirectly (membrane depolarization that opens L-type calcium channels). Glutamate release in t urn stimulates N-methyl-D-aspartate receptors, thus triggering the cascade of events leading to nitric oxide formation and possibly seizure production .