Null mutant analysis of responses to nicotine: Deletion of β2 nicotinic acetylcholine receptor subunit but not α7 subunit reduces sensitivity to nicotine-induced locomotor depression and hypothermia

The nicotinic acetylcholine receptor (nAChR) subtypes α4β2 and α7 comprise the majority of brain nicotine-binding sites. Classical genetic strategies using inbred mice and their hybrids suggest that nicotine's effects on locomotor activity and body temperature are influenced by α4β2 but not α7 receptors. To evaluate directly the role of these nicotinic subtypes on responses to nicotine, β2 and α7 null mutant (−/−) mice, as well as wild-type (+/+) and heterozygous (+/−) mice, were tested for baseline body temperature and locomotion and nicotine (07−1.5 mg/kg)-induced changes in these responses. Basal responses for these measures were similar for all β2 genotypes, but baseline Y-maze activity was higher in α7−/− mice compared with α7+/+ mice. Following nicotine injection, dose-dependent decreases in body temperature and locomotor activity were observed for all three genotypes of both β2 and α7 mice. Although responses in α7 mice did not differ among genotypes, β2 gene deletion was found to have a gene-dependent effect on nicotine's effects. β2−/7− mice were less sensitive to nicotine-induced locomotor depression and hypothermia at low nicotine doses (.25−.5 mg/kg) but were no different from β2+/+ mice at the highest doses tested (1.0−1.5 mg/kg). Residual responses at high nicotine doses in β2−/− mice as well as responses in all α7 and β2 mouse genotypes were mediated by nicotinic receptors, since mecamylamine (1.0 mg/kg) blocked all responses following 1.0 mg/kg nicotine. This finding suggests receptors that include the β2 nAChR subunit partially mediate nicotine's effects on locomotor activity and body temperature.