Abstract
Rationale
The effects of nicotine on cognitive processes may play an important role in nicotine addiction. Nicotine withdrawal impairs hippocampus-dependent learning and genetic factors influence this effect. However, the neural changes that contribute to these impairments are unknown. Chronic nicotine upregulates hippocampal nicotinic acetycholine receptors (nAChRs), which may contribute to cognitive deficits when nicotine administration ceases. If nAChR upregulation underlies withdrawal deficits in learning, then strains of mice exhibiting withdrawal deficits in hippocampus-dependent learning should also show upregulation of hippocampal nAChRs.
Objectives
Here, we examined the effects of nicotine withdrawal on fear conditioning and [3H]epibatidine binding in the dorsal and ventral hippocampus in two inbred mouse strains and their F1 hybrids.
Methods
Male C57BL/6NTac, 129S6/SvEvTac, and B6129SF1/Tac mice were administered chronic nicotine (18 mg/kg/day) for 12 days through osmotic pumps and then were trained and tested in fear conditioning 24 h after cessation of nicotine treatment.
Results
Nicotine withdrawal impaired hippocampus-dependent contextual conditioning in C57BL/6NTac mice but not 129S6/SvEvTac or B6129SF1/Tac mice; no changes were observed in hippocampus-independent cued fear conditioning. Upregulated [3H]epibatidine binding was found in the dorsal, but not ventral, hippocampus of C57BL/6NTac mice and in the ventral hippocampus of B6129SF1/Tac mice after chronic nicotine.
Conclusions
Upregulation of high-affinity binding sites in the dorsal hippocampus of C57BL/6NTac mice, the only strain that exhibited nAChR upregulation in this region and withdrawal deficits in contextual conditioning, suggests that upregulation of high-affinity binding sites in the dorsal hippocampus mediates, in part, nicotine withdrawal deficits in contextual conditioning and genetic background modulates these effects.
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Acknowledgments
The authors would like to acknowledge grant support from the National Institute on Drug Abuse (NIDA, DA024787, DA017949, TJG; DA026236, JRT) and the National Cancer Institute (CA143187, JAB). DSW was supported by a NIDA diversity supplement (DA024787-01A1S1). All procedures were in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals and US laws.
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The authors report no conflicts of interest.
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Wilkinson, D.S., Turner, J.R., Blendy, J.A. et al. Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus. Psychopharmacology 225, 201–208 (2013). https://doi.org/10.1007/s00213-012-2808-8
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DOI: https://doi.org/10.1007/s00213-012-2808-8