Long-term nicotine treatment down-regulates α6β2*nicotinic receptor expression and function in nucleus accumbens

Long-term nicotine exposure induces alterations in dopamine transmission in nucleus accumbens that sustain the reinforcing effects of smoking. One approach to understand the adaptive changes that arise involves measurement of endogenous dopamine release using voltammetry. We therefore treated rats for 2-3months with nicotine and examined alterations in nAChR subtype expression and electrically evoked dopamine release in rat nucleus accumbens shell, a region key in addiction. Long-term nicotine treatment selectively decreased stimulated 62* nAChR-mediated dopamine release compared with vehicle-treated rats. It also reduced 62* nAChRs, suggesting the receptor decline may contribute to the functional loss. This decreased response in release after chronic nicotine treatment was still partially sensitive to the agonist nicotine. Studies with an acetylcholinesterase inhibitor demonstrated that the response was also sensitive to increased endogenous acetylcholine. However, unlike the agonists, nAChR antagonists decreased dopamine release only in vehicle- but not nicotine-treated rats. As antagonists function by blocking the action of acetylcholine, their ineffectiveness suggests that reduced acetylcholine levels partly underlie the dampened 62* nAChR-mediated function in nicotine-treated rats. As long-term nicotine modifies dopamine release by decreasing 62* nAChRs and their function, these data suggest that interventions that target this subtype may be useful for treating nicotine dependence.