Nicotine enhances alcohol intake and dopaminergic responses through β2☆ and β4☆ nicotinic acetylcholine receptors

Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of beta 4(star) nAChRs, but not beta 2(star) nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (beta 2-/- and beta 4-/- mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in beta 2-/- and beta 4-/- mice, suggesting that nicotine triggers beta 2(star) and beta 4(star) nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs.