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The Journal of Neuroscience, September 21, 2005, 25(38):8708-8713; doi:10.1523/JNEUROSCI.2853-05.2005

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Behavioral/Systems/Cognitive
Withdrawal from Chronic Nicotine Administration Impairs Contextual Fear Conditioning in C57BL/6 Mice

Jennifer A. Davis,¹ John R. James,² Steven J. Siegel,³ and Thomas J. Gould¹

¹Department of Psychology, Neuroscience Program, Temple University, Philadelphia, Pennsylvania 19122, ²Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia 23298, and ³Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The effects of acute nicotine administration (0.09 mg/kg nicotine), chronic nicotine administration (6.3 mg/kg/d nicotine for 14 d), and withdrawal from chronic nicotine administration on fear conditioning in C57BL/6 mice were examined. Mice were trained using two coterminating conditioned stimulus (30 s; 85 dB white noise)–unconditioned stimulus (2 s; 0.57 mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. Acute nicotine administration enhanced contextual fear conditioning, chronic nicotine administration had no effect on contextual fear conditioning, and withdrawal from chronic nicotine administration impaired contextual fear conditioning. Plasma nicotine concentrations were similar after acute and chronic treatment and were within the range reported for smokers. During withdrawal, concentrations of nicotine were undetectable. An acute dose of nicotine (0.09 mg/kg) during withdrawal from chronic nicotine treatment reversed withdrawal-associated deficits in contextual fear conditioning. The results suggest that tolerance to the effects of nicotine on contextual fear conditioning develops with chronic nicotine treatment at a physiologically relevant dose, and withdrawal from this chronic nicotine treatment is associated with impairments in contextual fear conditioning. These findings provide a model of how the effects of nicotine on learning may contribute to the development and maintenance of nicotine addiction.

Key words: nicotine withdrawal; acetylcholine; hippocampus; addiction; learning; tolerance

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Received May 4, 2005; revised August 10, 2005; accepted August 14, 2005.

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