RT Journal Article SR Electronic T1 Long-Term Nicotine Treatment Differentially Regulates Striatal α6α4β2* and α6(Nonα4)β2* nAChR Expression and Function JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 844 OP 853 DO 10.1124/mol.108.048843 VO 74 IS 3 A1 Xiomara A. Perez A1 Tanuja Bordia A1 J. Michael McIntosh A1 Sharon R. Grady A1 Maryka Quik YR 2008 UL http://molpharm.aspetjournals.org/content/74/3/844.abstract AB Nicotine treatment has long been associated with alterations in α4β2* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of long-term nicotine treatment on the α6β2* 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 α6β2* 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, α6β2* nAChR blockade with α-conotoxin MII (α-CtxMII) decreased release with nonburst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate α6β2* nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, α6β2* nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the α6β2* nAChR subtypes altered with long-term nicotine treatment, we used the novel α-CtxMII analog E11A in combination with α4 nAChR knockout mice. 125I-α-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the α6α4β2* subtype but increased the α6(nonα4)β2* nAChR population. These data indicate that α6β2* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the α6(nonα4)β2* nAChR subtype and suggest that the α6α4β2* nAChR and/or α4β2* nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions. Thus, α6β2* nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease.