Ventral tegmental area α6β2 nicotinic acetylcholine receptors modulate phasic dopamine release in the nucleus accumbens core

Phasic dopamine (DA) signaling underlies reward learning. Cholinergic and glutamatergic inputs into the ventral tegmental area (VTA) are crucial for modulating burst firing activity and subsequent phasic DA release in the nucleus accumbens (NAc), but the specific VTA nicotinic receptor subtypes that regulate phasic DA release have not been identified. The goal was to determine the role of VTA N-methyl-d-aspartate receptors (NMDARs) and specific subtypes of nicotinic acetylcholine receptors (nAChRs) in regulating phasic DA release in the NAc core. Fast-scan cyclic voltammetry in anesthetized rats was combined with intra-VTA micro-infusion to evaluate the ability of glutamatergic and cholinergic drugs to modulate stimulated phasic DA release in the NAc core. VTA NMDAR blockade with AP-5 decreased, while VTA NMDAR activation with NMDA increased NAc peak phasic DA release. Intra-VTA administration of the nonspecific nAChR antagonist mecamylamine produced a persistent decrease in phasic DA release. Infusion of the alpha 6-selective antagonist alpha-conotoxin MII (alpha-ctx MII) produced a robust, but transient decrease in phasic DA, whereas infusion of selective doses of either the alpha 4 beta 2-selective antagonist, dihydro-beta-erythroidine, or the alpha 7 antagonist, methyllycaconitine, had no effect. Co-infusion of AP-5 and alpha-ctx MII produced a similar phasic DA decrease as either drug alone, with no additive effect. The results suggest that VTA alpha 6 beta 2 nAChRs, but not alpha 4 beta 2 or alpha 7 nAChRs, regulate phasic DA release in the NAc core and that VTA alpha 6 beta 2 nAChRs and NMDA receptors act at a common site or target to regulate NAc phasic DA signaling.