Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues

Rationale Cues associated with alcohol can elicit craving, support drug-seeking and precipitate relapse. Objectives We investigated the possible involvement of nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) in the conditioned reinforcing properties of ethanol-associated stimuli in the rat. Materials and methods First, using in vivo microdialysis, we analyzed the effect of VTA perfusion of the nonselective nAChR antagonist mecamylamine (MEC) or the selective alpha 4 beta 2* nAChR antagonist dihydro-beta-erythroidine (DH beta E) on the nucleus accumbens (nAc) dopaminergic response to the presentation of an ethanol-associated conditioned stimulus (CS). Second, rats were trained to associate a tone + light CS with the presentation of 10% ethanol and were subsequently tested on the acquisition of a new instrumental response with conditioned reinforcement (CR) after local VTA infusion of MEC, DH beta E, or alpha-Conotoxin MII (alpha-CtxMII, a selective alpha 3 beta 2* and alpha 6* nAChR antagonist). Results The ethanol-associated CS elevated nAc dopamine, an effect that was blocked by VTA perfusion of MEC but not DH beta E. Systemic administration of MEC or local VTA infusion of MEC or alpha-CtxMII selectively blocked ethanol-associated CR, whereas systemic DH beta E had no effect. Conclusions We hypothesize a novel mechanism by which alcohol-associated cues promote drug-seeking behavior via activation of dopamine-stimulating alpha-CtxMII-sensitive nAChRs in the VTA. Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse.