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6
4β2* and
6(Non
4)β2* nAChR Expression and FunctionThe 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
6
4β2* subtype but increased the
6(non
4)β2* nAChR population. These data indicate that
6β2* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the
6(non
4)β2* nAChR subtype and suggest that the
6
4β2* 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