title: The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation.
abstract: A predominant symptom of nicotine withdrawal is cognitive deficits, yet understanding of the neural basis for these deficits is limited. Withdrawal from chronic nicotine disrupts contextual learning in mice and this deficit is mediated by direct effects of nicotine in the hippocampus. Chronic nicotine treatment upregulates nicotinic acetylcholine receptors (nAChR); however, it is unknown whether upregulation is related to the observed withdrawal-induced cognitive deficits. If a relationship between altered learning and nAChR levels exists, changes in nAChR levels after cessation of nicotine treatment should match the duration of learning deficits. To test this hypothesis, mice were chronically administered 6.3mg/kg/day (freebase) nicotine for 12 days and trained in contextual fear conditioning on day 11 or between 1 to 16 days after withdrawal of treatment. Changes in [(125)I]-epibatidine binding at cytisine-sensitive and cytisine-resistant nAChRs and chronic nicotine-related changes in α4, α7, and β2 nAChR subunit mRNA expression were assessed. Chronic nicotine had no behavioral effect but withdrawal produced deficits in contextual fear conditioning that lasted 4 days. Nicotine withdrawal did not disrupt cued fear conditioning. Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding; upregulation continued after cessation of nicotine administration and the duration of upregulation during withdrawal paralleled the duration of behavioral changes. Changes in binding in cortex and cerebellum did not match behavioral changes. No changes in α4, α7, and β2 subunit mRNA expression were seen with chronic nicotine. Thus, nicotine withdrawal-related deficits in contextual learning are time-limited changes that are associated with temporal changes in upregulation of high-affinity nAChR binding.
authors.affiliation: Department of Psychology, Neuroscience Program, Temple University, Weiss Hall, 6th Floor, Philadelphia, PA 19122, USA. tgould@temple.edu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gould
authors.forename: George S
authors.initials: GS
authors.lastname: Portugal
authors.forename: Jessica M
authors.initials: JM
authors.lastname: André
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Tadman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: Justin W
authors.initials: JW
authors.lastname: Kenney
authors.forename: Emre
authors.initials: E
authors.lastname: Yildirim
authors.forename: Michael
authors.initials: M
authors.lastname: Adoff
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009538:Nicotine / Q000009:adverse effects*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D011978:Receptors, Nicotinic; D009538:Nicotine