Genetic influences on acute responses to nicotine and nicotine tolerance in the mouse

Abstract

Nineteen inbred mouse strains were tested for their relative sensitivity to nicotine's effects on respiratory rate, acoustic startle response, heart rate, Y-maze activity (crosses and rears) and body temperature. Separate animals were tested for their sensitivity to nicotine-induced seizures following IP injection or IV infusion. Dose-response curves were constructed for each measure. Large strain differences were obtained for all of these measures. Nicotine's effects on heart rate, Y-maze activity and body temperature segregated together into the various mouse strains whereas seizure sensitivity segregated independently which suggests that these responses are under separate genetic control. Evidence was obtained which suggests that nicotine-induced seizures are regulated, in part, by the number of hippocampal nicotinic receptors measured with alpha-bungarotoxin (BTX). Strain differences in the development of tolerance to nicotine were also observed. Four mouse strains were tested and one of these strains (C3H) did not exhibit tolerance to nicotine. The binding of (3H)nicotine and (125I)BTX increased in the brains of all four mouse strains. These changes may relate to tolerance in some mouse strains, but since C3H mice did not exhibit tolerance even though brain nicotinic receptors changed following chronic treatment, other explanations for the role of receptor changes in tolerance to nicotine must be sought.