Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson’s disease. This idea initially stemmed from the results of epidemiological studies which demonstrate that smoking is associated with a decreased incidence of Parkinson’s disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes, including α4β2, α6β2 and/or α7 containing nAChRs, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotine’s ability to reduce/halt the neuronal damage that arises in Parkinson’s disease. In addition to a potential neuroprotective action, nicotine also has anti-depressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinson’s disease.

Nicotine treatment has long been associated with alterations in ␣4␤2* nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of longterm nicotine treatment on the ␣6␤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 ␣6␤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, ␣6␤2* 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 ␣6␤2* nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, ␣6␤2* nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the ␣6␤2* nAChR subtypes altered with long-term nicotine treatment, we used the novel ␣-CtxMII analog E11A in combination with ␣4 nAChR knockout mice. 125 I-␣-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the ␣6␣4␤2* subtype but increased the ␣6(non␣4)␤2* nAChR population. These data indicate that ␣6␤2* nAChR-evoked dopamine release in nicotine-treated rats is mediated by the ␣6(non␣4)␤2* nAChR subtype and suggest that the ␣6␣4␤2* nAChR and/or ␣4␤2* nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions.