FROM ETHANOL TO SALSOLINOL: ROLE OF METABOLISM IN THE EFFECTS OF ETHANOL

The role of acetaldehyde in the effects of its parent compound, ethanol has gone a profound re-evaluation in the last five decades since the clinical observation that patients treated with antabuse, an aldehyde dehydrogenase inhibitor, could perceive more pleasurable effects when drinking small volumes of alcoholic beverages. However, the hypothesis that acetaldehyde could act as mediator of some of the effects of its parent compound did never reach a significant momentum until the discovery of catalase, the enzyme that converts ethanol into acetaldehyde within the brain. In this context, our research was aimed at investigating the role of acetaldehyde and of the acetaldehydedopamine (DA) conjugate, salsolinol, on the ability of ethanol to elicit Extracellular Signal regulated Kinases (ERK) in the nucleus accumbens, to exert motivational effects as assessed by conditioned place preference (CPP) and to excite dopamine neurons in the posterior ventral tegmental area (pVTA). The findings of our studies indicate that ethanol-derived acetaldehyde and salsolinol, similarly to ethanol, elicit ERK phosphorylation in the nucleus accumbens and CPP. Furthermore, electrophysiological experiments disclosed that, in order to excite DA neurons in the pVTA, a two-step sequential mechanism has to take place: 1) conversion of ethanol into acetaldehyde by the action of catalase and 2) condensation of acetaldehyde with DA to produce salsolinol. Overall these results support the view that the metabolism of ethanol plays a critical role its motivational effects and strongly indicate that this also accounts for its ability to excite DA neurons.