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First published on June 26, 2008; DOI: 10.1124/mol.108.048843

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Received for publication May 15, 2008.
Revised June 25, 2008.
Accepted for publication June 25, 2008.

Chronic nicotine treatment differentially regulates striatal {alpha}6{alpha}4{beta}2* and {alpha}6(non{alpha}4){beta}2* nAChR expression and function

Xiomara A Perez 1, Tanuja Bordia 1, J. Michael McIntosh 2, Sharon R. Grady 3, Maryka Quik 1*

1 The Parkinson's Institute 2 University of Utah 3 Institute for Behavioral Genetics

* Address correspondence to: E-mail: mquik{at}parkinsonsinstitute.org

Abstract

Nicotine treatment has long been associated with alterations in {alpha}4{beta}2* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of chronic nicotine treatment on the {alpha}6{beta}2* nAChR, a subtype specifically localized on dopaminergic neurons, is less clear. Here we used voltammetry, as well as receptor binding studies, to identify the effects of nicotine on striatal {alpha}6{beta}2* nAChR function and expression. Chronic nicotine via drinking water enhanced non-burst and burst endogenous dopamine release from rat striatal slices. In control animals, {alpha}6{beta}2* nAChR blockade with {alpha}-conotoxinMII ({alpha}-CtxMII) decreased release with non-burst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate {alpha}6{beta}2* nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, {alpha}6{beta}2* nAChR blockade elicited a similar pattern of dopamine release with non-burst and burst firing. To elucidate the {alpha}6{beta}2* nAChR subtypes altered with chronic nicotine treatment, we used the novel {alpha}-ctxMII analogue E11A, in combination with {alpha}4 nAChR knockout mice. 125I-{alpha}-ctxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the {alpha}6{alpha}4{beta}2* subtype, but increased the {alpha}6(non{alpha}4){beta}2* nAChR population. These data indicate that {alpha}6{beta}2* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the {alpha}6(non{alpha}4){beta}2* nAChR subtype, and suggest that the {alpha}6{alpha}4{beta}2* nAChR and/or {alpha}4{beta}2* nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions. Thus, {alpha}6{beta}2* nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease.


Key words: Dopamine, Nicotinic cholinergic, Drug tolerance/dependence




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