Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues
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Cues associated with alcohol can elicit craving, support drug-seeking and precipitate relapse.
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 α4β2* nAChR antagonist dihydro-β-erythroidine (DHβE) 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, DHβE, or α-Conotoxin MII (α-CtxMII, a selective α3β2* and α6* nAChR antagonist).
The ethanol-associated CS elevated nAc dopamine, an effect that was blocked by VTA perfusion of MEC but not DHβE. Systemic administration of MEC or local VTA infusion of MEC or α-CtxMII selectively blocked ethanol-associated CR, whereas systemic DHβE had no effect.
We hypothesize a novel mechanism by which alcohol-associated cues promote drug-seeking behavior via activation of dopamine-stimulating α-CtxMII-sensitive nAChRs in the VTA. Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse.
KeywordsAcetylcholine Ventral tegmental area Addiction Alcohol Conditioned reinforcement Dopamine Nicotinic receptor Nucleus accumbens
Financial support for this work was obtained from the Swedish Medical Research Council no:s 11583 and 4247, the Swedish Labour Market Insurance (AFA) support for biomedical alcohol research, the Alcohol Research Council of the Swedish Alcohol Retailing Monopoly, NIDA 2 R01 10765-04A1, PHS NIH (DA15222, DA11717 and AA15632 to JRT and MH53631 to JMM), Gunnar och Märtha Bergendahls Stiftelse, the Council for Medical Tobacco Research—Swedish Match, Wilhelm och Martina Lundgrens vetenskapsfond, Kungliga Vetenskaps—och Vitterhets-Samhället i Göteborg, Helge Ax:son Johnsons Stiftelse, Längmanska kulturfonden, Jubileumsfonden, Iris Jonzén-Sandbloms och Greta Jonzéns Stiftelse & Stiftelsen KvinnorKan, Axel Linders stiftelse and Apotekarsocieteten. We are grateful for the generous gift of mecamylamine from the NIDA drug supply program, Bethesda, MD, USA.
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