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.
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. Conditioning consisted of two white noise (30 s, 85 dB)-foot-shock (2 s, 0.57 mA) pairings. Saline or ethanol was administered to C57BL/6 mice 15 min before training and saline or nicotine was administered 5 min before training or before training and testing. The ability of the high-affinity nicotinic acetylcholinergic receptor (nAChR) antagonist dihydro-beta-erythroidine (DHbetaE) to modulate the effects of ethanol and nicotine was also tested; saline or DHbetaE was administered 25 (injection) or 15 (infusion) minutes before training or before training and testing. 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-naive mice. DHbetaE blocked the effects of nicotine on ethanol-induced deficits; interestingly, DHbetaE alone and co-administration of subthreshold doses of DHbetaE and nicotine also ameliorated ethanol-induced deficits but failed to enhance learning. Finally, DHbetaE failed to ameliorate ethanol-induced deficits in beta2 nAChR subunit knockout mice. 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 beta2 subunit-containing nAChRs.
Gulick
Danielle
D
Department of Psychology, Neuroscience Program, Center for Substance Abuse Research, Temple University, Philadelphia, PA 19122, USA.
Gould
Thomas J
TJ
D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004079:Dihydro-beta-Erythroidine / Q000008:administration & dosage / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005239:Fear; D005260:Female; D006179:Gyrus Cinguli / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D002492:Central Nervous System Depressants; D004079:Dihydro-beta-Erythroidine; D000431:Ethanol; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic