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Vol. 291, Issue 3, 1284-1291, December 1999
Departments of Pharmacology and Toxicology (M.I.D., W.G., B.R.M.)
and Medicinal Chemistry (M.D.), Medical College of Virginia of Virginia
Commonwealth University, Richmond, Virginia
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-
-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 
7 along with other nicotinic receptor subunits.
Indeed, MLA, an 7-antagonist, blocked the effects of nicotine after
peripheral and central administration. The extent of 42-receptor
subtype involvement in nicotine-induced seizures was difficult to
assess. On one hand, we observed that dihydro--erythroidine (a
competitive antagonist) failed to block the effects of nicotine. In
addition, a poor correlation was found between binding affinity for
3H-nicotine-labeled sites (predominantly 42) 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 7 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.
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