Potential role of the α4 and α6 nicotinic receptor subunits in regulating nicotine-induced seizures

Several studies have shown that genetic factors influence sensitivity to nicotine-induced seizures in the mouse. We used recombinant inbred (RI) strains derived from the Long-Sleep (LS) and Short-Sleep (SS) mouse lines to assess the possibility that polymorphisms associated with one or more of the nicotinic receptors cosegregate with differential sensitivity to nicotine-induced seizures. Restriction fragment length polymorphisms (RFLPs) associated with the alpha 2, alpha 3, alpha 4, alpha 5, and alpha 6 nicotinic receptors were identified in the LS and SS mouse lines, but the RI strains were polymorphic for only the alpha 4 and alpha 6 RFLPs. The RI strains were tested for sensitivity to nicotine-induced seizures. Strain and gender effects on seizure sensitivity were obtained as assessed by ED50 values and latency to seizure. Those RI strains with the LS-like alpha 4 RFLP were, on average, more sensitive to nicotine-induced seizures than were those RI strains with SS-like alpha 4 RFLP. The alpha 6 nicotine receptor may also play a role in modulating nicotine-induced seizures, but this effect is markedly influenced by gender. Females of the RI strains with the LS-like alpha 6 RFLP were more sensitive to nicotine than were females of the strains with the SS-like alpha 6 RFLP. Similar trends were seen in the males, but these trends were not significant. Thus, these strain differences may be due to polymorphisms associated with both the alpha 4 and alpha 6 nicotinic receptors, but gender also plays an important role in regulating sensitivity to nicotine-induced seizure.