Received for publication March 13, 2006.
Revised April 17, 2006.
Accepted for publication April 17, 2006.

Differential regulation of mesolimbic 3*/62* and 42* nAChR sites and function after long-term oral nicotine to monkeys

Abstract

Since the mesolimbic dopamine system plays a critical role in nicotine addiction/reinforcement and since 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 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 3/62* and 42* 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 42* and 3/62* nAChRs were measured using ¹²⁵I-epibatidine, ¹²⁵I-A85380 and ¹²⁵I--conotoxinMII autoradiography. Chronic nicotine treatment, which led to plasma nicotine levels in the range of smokers, significantly increased nucleus accumbens 42* nAChR sites and function compared to control. By contrast, this treatment did not significantly change 3/62* nAChR sites or evoked dopamine release in this region compared to control. These data are thus distinct from previous results in striatum in which the same nicotine treatment paradigm decreased striatal 3/62* nAChR sites and function. The finding that long-term nicotine treatment selectively modulates 42*, and not 3/62*, nAChR expression in primate nucleus accumbens, is consistent with the results of studies in nicotinic receptor mutant mice implicating the 42* nAChR subtype in nicotine-mediated addiction.

Key words: Nicotinic, alpha-conotoxinMII, mesolimbic, nicotine, nonhuman primates, nucleus accumbens

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