VTA circuitry sustains opposite responses of dopaminergic neurons to drugs of abuse

AIMS: Nicotine, the main psychoactive compound of tobacco, binds on cationic nicotinic receptors (nAChRs) to increase the firing rate of dopaminergic (DA) neurons of the ventral tegmental area (VTA), leading to higher release of DA in target structures and positive reinforcement. Besides rewarding properties, nicotine also promotes negative effects. Recently, we showed heterogeneity in nicotine-induced responses on VTA DA subpopulations targeting nucleus accumbens (NAc) and amygdala (AMg) nuclei. NAc-projecting DA neurons are activated by nicotine and their optogenetic activation is reinforcing. AMg-projecting DA neurons are inhibited by nicotine and their optogenetic silencing is anxiogenic.We address 1) if alcohol, known for its rewarding and anxiolytic/anxiogenic properties, also produces distinct responses on DA subpopulations, and 2) if a circuit-based mechanism could underly drug-induced inhibition. METHODS: Combining in vivo juxtacellular or ex vivo patch-clamp recordings with injections of retrograde tracers, we investigated the mechanism underlying response profiles to ethanol of NAc or AMg-projecting DA neurons and the role of drug-induced inhibition on behavior. RESULTS: We demonstrated that alcohol induces two opposite responses, such as nicotine, on the same segregated DA subpopulations. We showed that drug-induced inhibition is a consequence of activation of NAc-projecting DA neurons. Finally, we started to investigate the functional role of DA inhibition on reinforcement and anxiety-like behaviors. CONCLUSION: These results highlight heterogeneity of drug impact on DA subpopulations and raise the question of the role it might play in the balance between the drugs positive and negative effects that regulates their use.