Received for publication November 23, 2004.
Revised January 10, 2005.
Accepted for publication January 11, 2005.

Nicotinic receptor subtypes in rat hippocampal slices are differentially sensitive to desensitization and early in vivo functional upregulation by nicotine and to block by bupropion

Abstract

To identify the brain nicotinic acetylcholine receptor (nAChR) subtypes that may be involved in nicotine addiction, we investigated the actions of bupropion, a drug used in cigarette smoking cessation programs, and nicotine on three pharmacologically identified nAChRs in rat hippocampal slices namely Type IA, Type II and Type III nAChRs, likely representing 7, 42, and 34 subunits respectively. Using whole-cell patch-clamp recordings from interneurons of acute hippocampal slices prepared from male rat pups, we studied the effect of nicotine on in vivo upregulation and in vitro desensitization of nAChRs. Two subcutaneous injections of nicotine (0.586 mg/kg free base, in less than a day) to rats at postnatal days 14-15 significantly enhanced the magnitude of functional responses arising from Type III and Type II, but not Type IA nAChRs. This treatment did not increase the functional affinity for acetylcholine at Type II nAChRs. A single injection of nicotine also produced a significant increase in Type III nAChR response. In addition, Type III and Type II, but not Type IA nAChRs, are desensitized by in vitro exposure to nicotine at concentrations found in the venous blood of cigarette smokers. Bupropion at 1 µM produced 56%, 15% and 0% inhibition of Type III, Type II and Type IA nAChR responses, respectively, in the slices. Our results suggest that in vivo-nicotine-induced nAChR upregulation observed in neurons of intact brain tissue is a physiologically relevant phenomenon, and that early upregulation of Type III and Type II nAChRs could be an important biological signal in nicotine addiction.

Key words: bupropion, choline, desensitization, nicotine, nicotinic receptors, upregulation

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