Alcohol as Prodrug of Salsolinol: The Long-Sought Alcohol’s Key Mechanism of Action on Dopamine Neurons

Alcohol, the psychopharmacologically active ingredient of alcoholic drinks responsible of their addictive potential, represents a threat to both individual and public health being a risk factor of a number of serious pathological conditions spanning, besides addiction, from liver and cardiovascular diseases to neurological disorders and cancer. The occurrence of altered behaviors toward uncontrolled alcohol intake is a complex and not yet fully understood phenomenon. Notwithstanding, it is unanimously recognized that alcohol’s addictive potential resides in its efficiency for activating the mesolimbic dopamine system, an ability that involves several central neurotransmitter systems although the specific mechanism and site of action are still the subject of intense research. In this regard, recent and compelling evidence points to the two-step metabolic conversion, in the posterior ventral tegmental area (pVTA), of alcohol into acetaldehyde and salsolinol, the latter being the product of condensation between acetaldehyde and dopamine, as the key mechanism for eliciting dopamine transmission in the nucleus accumbens and dopamine-mediated behaviors through the involvement of μ opioid receptors. This chapter emphasizes the strategic role of alcohol metabolism and recapitulates the most recent advances in support of the evidence that alcohol is the prodrug of salsolinol for its actions on the dopamine system and hence for its reinforcing effects and addictive liability.