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.