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Vol. 293, Issue 1, 67-74, April 2000

Potential Role of the alpha 4 and alpha 6 Nicotinic Receptor Subunits in Regulating Nicotine-Induced Seizures1

Jerry A. Stitzel, Melissa Jimenez, Michael J. Marks, Theresa Tritto and Allan C. Collins

Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado

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.

1 This work was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA11156) and the National Institute on Drug Abuse (DA10156). A.C.C. is supported in part by a Research Scientist Award from the National Institute on Drug Abuse (DA00197).

0022-3565/00/2931-0067$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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