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Dissociation of tolerance and nicotine withdrawal-associated deficits in contextual fear.

Authors
  • Gould, Thomas J1
  • Wilkinson, Derek S2
  • Yildirim, Emre2
  • Blendy, Julie A3
  • Adoff, Michael D2
  • 1 Department of Psychology, Weiss Hall, Neuroscience Program, Temple University, Philadelphia, PA 19122, USA. Electronic address: [email protected]
  • 2 Department of Psychology, Weiss Hall, Neuroscience Program, Temple University, Philadelphia, PA 19122, USA.
  • 3 Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Type
Published Article
Journal
Brain research
Publication Date
Apr 22, 2014
Volume
1559
Pages
1–10
Identifiers
DOI: 10.1016/j.brainres.2014.02.038
PMID: 24594018
Source
Medline
Keywords
License
Unknown

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.

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