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Ethyl alcohol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend, at least partially, on the activation of the mesolimbic dopaminergic system. On the other hand, acetaldehyde (ACD), EtOH's first metabolite, has been classically considered aversive and useful in the pharmacologic therapy of alcoholics. Here we show that EtOH-derived ACD is necessary for EtOH-induced place preference, a preclinical test with high predictive validity for reward liability. We also found that ACD is essential for EtOH-increased microdialysate dopamine (DA) levels in the nucleus accumbens (NAcc), and that this effect is mimicked by ACD administration to the intraventral tegmental area (VTA). Furthermore, in vitro, ACD enhances VTA DA neuronal firing. Coherently, EtOH-stimulating properties on DA neurons are prevented by pharmacologic blockade of local catalase: the main metabolic step for biotransformation of EtOH into ACD in the central nervous system. These results provide in vivo and in vitro evidence for a key role of ACD in EtOH motivational properties and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD, by increasing VTA DA neuronal activity, would oppose its well-known peripherally originating aversive properties. These findings could help in devising new effective pharmacologic therapies in alcoholism.

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Our results underscore the role of ACD on EtOH-induced stimulation of DA mesoaccumbens system and support the notion that thiol compounds such as Lcys, by modulating EtOH-derived ACD bioavailability, would blunt EtOH rewarding properties.