title: Long-term nicotine treatment differentially regulates striatal alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR expression and function.
abstract: Nicotine treatment has long been associated with alterations in alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of long-term nicotine treatment on the alpha6beta2(*) 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 alpha6beta2(*) nAChR function and expression. Long-term nicotine treatment via drinking water enhanced nonburst and burst endogenous dopamine release from rat striatal slices. In control animals, alpha6beta2(*) nAChR blockade with alpha-conotoxin MII (alpha-CtxMII) decreased release with nonburst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate alpha6beta2(*) nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, alpha6beta2(*) nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the alpha6beta2(*) nAChR subtypes altered with long-term nicotine treatment, we used the novel alpha-CtxMII analog E11A in combination with alpha4 nAChR knockout mice. (125)I-alpha-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the alpha6alpha4beta2(*) subtype but increased the alpha6(nonalpha4)beta2(*) nAChR population. These data indicate that alpha6beta2(*) nAChR-evoked dopamine release in nicotine-treated rats is mediated by the alpha6(nonalpha4)beta2(*) nAChR subtype and suggest that the alpha6alpha4beta2(*) nAChR and/or alpha4beta2(*) nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions. Thus, alpha6beta2(*) nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease.
authors.affiliation: The Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94085, USA.
authors.forename: Xiomara A
authors.initials: XA
authors.lastname: Perez
authors.forename: Tanuja
authors.initials: T
authors.lastname: Bordia
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004594:Electrophysiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors; D014867:Water
chemical_list: D004298:Dopamine; D009538:Nicotine; D011978:Receptors, Nicotinic; D014867:Water; C559463:alpha6beta2 nicotinic acetylcholine receptor; C104518:nicotinic receptor alpha6