Genetic and pharmacological strategies identify a behavioral function of neuronal nicotinic receptors

The studies outlined here used pharmacological and genetic approaches to attempt to identify the nicotinic receptors that modulate nicotine-induced seizures. Full-blown clonic-tonic seizures were induced by intracerebroventricular (i.c.v.) injection of nicotine, the alpha 4 beta 2 selective agonist ABT-418 and the alpha 7-selective GTS-21. Cytisine, which is a partial agonist at alpha 4 beta 2-type receptors, produced partial seizures. DH beta E and MLA did not block nicotine-induced seizures. Instead, both antagonists caused seizures. Restriction fragment length polymorphisms (RFLPs) for the alpha 7 receptor were identified in two inbred strains (C3H and DBA) that differ in sensitivity to nicotine-induced seizures. F2 mice derived from a C3H x DBA cross that were homozygous for the C3H variant of the alpha 7 RFLP were more sensitive to nicotine-induced seizures than were F2 mice that were homozygous for the DBA RFLP. In a study that used RI strains derived from two selectively bred mouse lines (LS and SS), an association between sensitivity to nicotine-induced seizures and an RFLP associated with the alpha 4 gene was found. These data support the assertion that both alpha 4 and alpha 7 receptor types are involved in modulating convulsions produced by nicotine. (C) 2000 Elsevier Science B.V. All rights reserved.