The hippocampus and cingulate cortex differentially mediate the effects of nicotine on learning versus on ethanol-induced learning deficits via different effects at nicotinic receptors

INTRODUCTION: The 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. METHODS: Conditioning 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. RESULTS: Infusion 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. CONCLUSIONS: These 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.