Long-term nicotine treatment differentially regulates striatal α6α4β2* and α6(nonα4)β2* nAChR expression and function

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 long-term 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. Long-term nicotine treatment via drinking water enhanced nonburst and burst endogenous dopamine release from rat striatal slices. In control animals, alpha 6 beta 2* 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 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 nonburst and burst firing. To elucidate the alpha 6 beta 2* nAChR subtypes altered with long-term nicotine treatment, we used the novel alpha-CtxMII analog E11A in combination with alpha 4 nAChR knockout mice. (125)I-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.