Role of neuronal nicotinic receptors in the effects of nicotine and ethanol on contextual fear conditioning

Abstract Nicotine can enhance contextual learning while ethanol impairs some forms of learning. Nicotine can overcome some of the impairing effects of ethanol when the two drugs are co-administered. The specific brain nicotinic acetylcholine receptors (nAChRs) that mediate nicotine's effects on contextual learning and whether any of ethanol's actions are mediated by nAChRs are unknown. The potential roles of nAChRs in contextual and cued fear conditioning as well as the effects of nicotine, ethanol, or co-administration of nicotine and ethanol were examined in wild type and homozygous null mutant mice from α7, β2, β3, and β4 mouse lines at 24 h after training. Nicotine was given prior to training and testing, whereas ethanol was given only before training. Nicotine enhanced contextual learning in both α7 wild types and mutants when mice were trained at 0.17 mA, but not 0.35 mA. Mutants lacking the α7 subunit were less sensitive to the memory impairing effects of ethanol trained at 0.35 mA. β2 Null mutants receiving saline showed a small, but significant, impairment in contextual learning compared with wild type littermates when the shock stimulus was 0.35 mA. β2 Null mutant mice also did not respond to the cognitive enhancing effects of nicotine alone, or after ethanol administration. β3 and β4 null mutants did not differ from wild types either after saline or any of drug treatments, These results show that β2-containing nAChRs, but not β3- or β4-containing receptors, mediate the enhancing effects of nicotine on contextual learning and confirm previous studies implicating β2 in other forms of learning. A new role for α7 nAChRs in regulating sensitivity to the cognitive disrupting effects of ethanol is proposed.