title: Dissociation of tolerance and nicotine withdrawal-associated deficits in contextual fear.
abstract: Nicotine addiction is associated with the development of tolerance and the emergence of withdrawal symptoms upon cessation of chronic nicotine administration. Changes in cognition, including deficits in learning, are one of the most common withdrawal symptoms reported by smokers. However, the neural substrates of tolerance to the effects of nicotine on learning and the substrates of withdrawal deficits in learning are unknown, and in fact it is unclear whether a common mechanism is involved in both. The present study tested the hypothesis that tolerance and withdrawal are separate processes and that nicotinic acetylcholine receptor (nAChR) upregulation underlies changes in learning associated with withdrawal but not tolerance. C57BL/6 male mice were administered a dose of nicotine (3, 6.3, 12, or 24 mg/kg/d) chronically for varying days and tested for the onset of tolerance to the effects of nicotine on learning. Follow up experiments examined the number of days of chronic nicotine treatment required to produce withdrawal deficits in learning and a significant increase in [(3)H] epibatidine binding in the hippocampus indicative of receptor upregulation. The results indicate that tolerance onset was influenced by dose of chronic nicotine, that tolerance occurred before withdrawal deficits in learning emerged, and that nAChR upregulation in the dorsal hippocampus was associated with withdrawal but not tolerance. This suggests that for the effects of nicotine on learning, tolerance and withdrawal involve different substrates. These findings are discussed in terms of implications for development of therapeutics that target symptoms of nicotine addiction and for theories of addiction.
authors.affiliation: Department of Psychology, Weiss Hall, Neuroscience Program, Temple University, Philadelphia, PA 19122, USA. Electronic address: tgould@temple.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gould
authors.affiliation: Department of Psychology, Weiss Hall, Neuroscience Program, Temple University, Philadelphia, PA 19122, USA.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Wilkinson
authors.affiliation: Department of Psychology, Weiss Hall, Neuroscience Program, Temple University, Philadelphia, PA 19122, USA.
authors.forename: Emre
authors.initials: E
authors.lastname: Yildirim
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Blendy
authors.affiliation: Department of Psychology, Weiss Hall, Neuroscience Program, Temple University, Philadelphia, PA 19122, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Adoff
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013997:Time Factors; D014029:Tobacco Use Disorder / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: Acetylcholine; Addiction; Cognition; Learning; Receptor binding; Withdrawal