Nicotinic receptor subtypes in rat hippocampal slices are differentially sensitive to desensitization and early in vivo functional up-regulation by nicotine and to block by bupropion.
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 alpha7, alpha4beta2, and alpha3beta4 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 up-regulation 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 to 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 muM 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 up-regulation observed in neurons of intact brain tissue is a physiologically relevant phenomenon and that early up-regulation of type III and type II nAChRs could be an important biological signal in nicotine addiction.
Alkondon
Manickavasagom
M
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, 21201, USA. malko001@umaryland.edu
Albuquerque
Edson X
EX
D000818:Animals; D016642:Bupropion / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D016642:Bupropion; D009538:Nicotine