Increases in α4* but not α3*/α6* nicotinic receptor sites and function in the primate striatum following chronic oral nicotine treatment

Knowledge of the effects of chronic nicotine is critical considering its widespread use in tobacco products and smoking cessation therapies. Although nicotine is well known to up-regulate a4* nAChR sites and function in the cortex, its actions in the striatum are uncertain because of the presence of multiple subtypes with potentially opposing effects. We therefore investigated the effect of long-term nicotine treatment on nAChR sites and function in the primate striatum, which offers the advantage of similar proportions of a3*/a6* and a4* nAChRs. Nicotine was given in drinking water, which resembles smoking in its intermittent but chronic delivery. Plasma nicotine and cotinine levels were similar to smokers. Chronic nicotine treatment (> 6 months) enhanced a4* nAChR-evoked [ 3 H]dopamine release in striatal subregions, with an overall pattern of increase throughout the striatum when normalized to uptake. This increase correlated with elevated striatal a4* nAChRs. Under the same conditions, striatal a3*/a6* nAChR sites and function were decreased or unchanged. These divergent actions of chronic nicotine treatment on a4* versus a6* nAChRs, as well as effects on dopamine uptake, allow for a complex control of striatal activity to maintain dopaminergic function. Such knowledge is important for understanding nicotine dependence and the consequences of nicotine administration for the treatment of neurological disorders.