Perez_2012_J.Pharmacol.Exp.Ther_342_335

Tobacco use is a leading cause of preventable deaths worldwide. However, current smoking cessation therapies have very limited long-term success rates. Considerable research effort is therefore focused on identification of central nervous system changes with nicotine exposure because this may lead to more successful treatment options. Although recent work suggests that alpha6beta2* nicotinic acetylcholine receptors (nAChRs) play a dominant role in dopaminergic function in rodent nucleus accumbens, the effects of long-term nicotine exposure remain to be determined. Here, we used cyclic voltammetry to investigate alpha6beta2* nAChR-mediated release with long-term nicotine treatment in nonhuman primate nucleus accumbens shell. Control studies showed that nAChR-mediated dopamine release occurs predominantly through the alpha6beta2* receptor subtype. Unexpectedly, there was a complete loss of alpha6beta2* nAChR-mediated activity after several months of nicotine treatment. This decline in function was observed with both single- and multiple-pulse-stimulated dopamine release. Paired-pulse studies showed that the facilitation of dopamine release with multiple pulsing observed in controls in the presence of nAChR antagonist was lost with long-term nicotine treatment. Nicotine-evoked [(3)H]dopamine release from nucleus accumbens synaptosomes was similar in nicotine- and vehicle-treated monkeys, indicating that long-term nicotine administration does not directly modify alpha6beta2* nAChR-mediated dopamine release. Dopamine uptake rates, as well as dopamine transporter and alpha6beta2* nAChRs levels, were also not changed with nicotine administration. These data indicate that nicotine exposure, as occurs with smoking, has major effects on cellular mechanisms linked to alpha6beta2* nAChR-mediated dopamine release and that this receptor subtype may represent a novel therapeutic target for smoking cessation.