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Eur J Neurosci. 2009 Jan;29(2):377-87. doi: 10.1111/j.1460-9568.2008.06580.x.

Nicotine withdrawal-induced deficits in trace fear conditioning in C57BL/6 mice--a role for high-affinity beta2 subunit-containing nicotinic acetylcholine receptors.

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Center for Substance Abuse Research & Department of Psychology, 1701n 13th, Weiss Hall, 657, Temple University, Philadelphia, PA 19122, USA.


Nicotine alters cognitive processes that include working memory and long-term memory. Trace fear conditioning may involve working memory during acquisition while also allowing the assessment of long-term memory. The present study used trace fear conditioning in C57BL/6 mice to investigate the effects of acute nicotine, chronic nicotine and withdrawal of chronic nicotine on processes active during acquisition and recall 24 h later and to examine the nicotinic acetylcholine receptor subtypes (nAChRs) involved in withdrawal deficits in trace fear conditioning. During training, acute nicotine (0.09 mg/kg) enhanced, but chronic nicotine (6.3 mg/kg/day, 13 days) and withdrawal of chronic nicotine (6.3 mg/kg/day, 12 days) had no significant effect on, acquisition of trace conditioning. At recall, acute treatment enhanced conditioning while chronic nicotine had no effect and withdrawal of chronic nicotine resulted in deficits. Antagonist-precipitated withdrawal was used to characterize the nAChRs involved in the withdrawal deficits. The low-affinity nAChR antagonist MLA (1.5, 3 or 9 mg/kg) had no effect on trace fear conditioning, but the high-affinity nAChR antagonist DHbetaE (3 mg/kg) precipitated deficits in trace fear conditioning if administered at training or training and testing, but not if administered at testing alone. The beta2 nAChR subunit is involved in the withdrawal effects as withdrawal of chronic nicotine produced deficits in trace fear conditioning in wildtype but not in beta2-knockout mice. Thus, nicotine alters processes involved in both acquisition and long-term memory of trace fear conditioning, and high-affinity beta2 subunit-containing nAChRs are critically involved in the effects of nicotine withdrawal on trace fear conditioning.

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