Differential Regulation of Mesolimbic α3/α6β2 and α4β2 Nicotinic Acetylcholine Receptor Sites and Function after Long-Term Oral Nicotine to Monkeys

Because the mesolimbic dopamine system plays a critical role in nicotine addiction/reinforcement and because nicotinic receptors regulate dopamine release, we initiated a study to evaluate the long-term effects of nicotine (>6 months at the final dose) on nicotinic acetylcholine receptor (nAChR) sites and function in the nucleus accumbens of nonhuman primates. Nicotine was given in the drinking water as this mode of administration is long-term but intermittent, thus resembling smoking in this aspect. We determined the effects of nicotine treatment on function and binding of the α3/α6β2* and α4β2* nAChRs subtypes in nucleus accumbens, a region directly implicated in the addictive effects of nicotine. To evaluate function, we measured nicotine and K⁺-evoked [³H]dopamine release from nucleus accumbens synaptosomes. Changes in α4β2* and α3/α6β2* nAChRs were measured using ¹²⁵I-epibatidine, [¹²⁵I]A85380 [5-[¹²⁵I]iodo-3(2(S)-azetidinylmethoxy) pyridine] and ¹²⁵I-α-conotoxin MII autoradiography. Chronic nicotine treatment, which led to plasma nicotine levels in the range of smokers, significantly increased nucleus accumbens α4β2* nAChR sites and function compared with control. By contrast, this treatment did not significantly change α3/α6β2* nAChR sites or evoked dopamine release in this region compared with control. Thus, these data are distinct from previous results in striatum in which the same nicotine treatment paradigm decreased striatal α3/α6β2* nAChR sites and function. The finding that long-term nicotine treatment selectively modulates α4β2* and not α3/α6β2* nAChR expression in primate nucleus accumbens is consistent with the results of studies in nicotinic receptor mutant mice implicating the α4β2* nAChR subtype in nicotine-mediated addiction.