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Long-Term Nicotine Treatment Differentially Regulates Striatal 64β2^* and 6(Non4)β2^* nAChR Expression and Function

The Parkinson's Institute, Sunnyvale, California (X.A.P., T.B., M.Q.); Department of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.); and Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (S.R.G.).

Nicotine treatment has long been associated with alterations in 4β2^* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of long-term nicotine treatment on the 6β2^* 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 6β2^* 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, 6β2^* nAChR blockade with -conotoxin MII (-CtxMII) decreased release with nonburst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate 6β2^* nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, 6β2^* nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the 6β2^* nAChR subtypes altered with long-term nicotine treatment, we used the novel -CtxMII analog E11A in combination with 4 nAChR knockout mice. ¹²⁵I--CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the 64β2^* subtype but increased the 6(non4)β2^* nAChR population. These data indicate that 6β2^* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the 6(non4)β2^* nAChR subtype and suggest that the 64β2^* nAChR and/or 4β2^* nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions. Thus, 6β2^* nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease.

Address correspondence to: Maryka Quik, The Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94085. E-mail: mquik{at}parkinsonsinstitute.org