The Hippocampus and Cingulate Cortex Differentially Mediate the Effects of Nicotine on Learning Versus on Ethanol-Induced Learning Deficits Through Different Effects at Nicotinic Receptors

Abstract

IntroductionThe current study examined the effects of nicotine infusion into the dorsal hippocampus or anterior cingulate on fear conditioning and on ethanol-induced deficits in fear conditioning, and whether these effects involved receptor activation or inactivation.MethodsConditioning consisted of two white noise (30 seconds, 85 dB)–foot shock (2 seconds, 0.57 mA) pairings. Saline or ethanol was administered to C57BL/6 mice 15 minutes before training and saline or nicotine was administered 5 minutes before training or before training and testing. The ability of the high-affinity nicotinic acetylcholinergic receptor (nAChR) antagonist dihydro-beta-erythroidine (DHβE) to modulate the effects of ethanol and nicotine was also tested; saline or DHβE was administered 25 (injection) or 15 (infusion) minutes before training or before training and testing.ResultsInfusion of nicotine into the hippocampus enhanced contextual fear conditioning but had no effect on ethanol-induced learning deficits. Infusion of nicotine into the anterior cingulate ameliorated ethanol-induced deficits in contextual and cued fear conditioning but had no effect on learning in ethanol-naïve mice. DHβE blocked the effects of nicotine on ethanol-induced deficits; interestingly, DHβE alone and co-administration of sub-threshold doses of DHβE and nicotine also ameliorated ethanol-induced deficits but failed to enhance learning. Finally, DHβE failed to ameliorate ethanol-induced deficits in β2 nAChR subunit knockout mice.ConclusionsThese results suggest that nicotine acts in the hippocampus to enhance contextual learning, but acts in the cingulate to ameliorate ethanol-induced learning deficits through inactivation of high-affinity β2 subunit-containing nAChRs.