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

asterisk indicates the possible presence of other nicotinic subunits in the receptor complex. ABSTRACT Nicotine treatment has long been associated with alterations in α4β2* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of chronic 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. Chronic nicotine via drinking water enhanced non-burst and burst endogenous dopamine release from rat striatal slices. In control animals, α6β2* nAChR blockade with α-conotoxinMII (α-CtxMII) decreased release with non-burst 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 non-burst and burst firing. To elucidate the α6β2* nAChR subtypes altered with chronic nicotine treatment, we used the novel α-CtxMII analogue E11A, in combination with α4 nAChR knockout mice. 125 I-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.