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In spite of the enormous scientific interest raised by its widespread use, ethanol still remains, from the pharmacological and toxicological standpoints, an elusive molecule. Accordingly, its effects cannot be attributed only to actions onto specific targets (receptors, enzymes, channels, etc.) nor to the unique involvement of neurotransmitter systems (glutamate, GABA, dopamine, opioid peptides, etc.). Both the pharmacological and toxicological effects of ethanol, in fact, have also been related to its metabolic conversion into acetaldehyde, a highly reactive molecule that, besides other properties, shows the ability to condensate, spontaneously or enzymatically, with nucleophilic compounds to form tetrahydroisoquinolines. Among the latter, salsolinol has recently received a great deal of attention both for its neurobiological properties potentially related to alcoholism development and for its neurotoxicity. Accordingly, although detected at very low concentrations in ethanol-naïve subjects, salsolinol appears particularly enriched in the brain, in dopamine-containing nuclei where its main metabolites, N-methyl-salsolinol and 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, may exert cytotoxic effects. This chapter recapitulates the most compelling evidence that relates ethanol-derived salsolinol to the neurobiological basis of alcoholism and to the suggested emergence of neurological disorders associated, in particular, to dopamine neurodegeneration.

After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths. Accordingly, the effects of acetaldehyde, after its systemic or central administration and as obtained following ethanol metabolism, looked as they were extensively characterized. However, almost 5 years after this research appeared at its highest momentum, the investigations on this topic have been revitalized on at least three main directions: (1) the role and the behavioral significance of acetaldehyde in different phases of ethanol self-administration and in voluntary ethanol consumption; (2) the distinction, in the central effects of ethanol, between those arising from its non-metabolized fraction and those attributable to ethanol-derived acetaldehyde; and (3) the role of the acetaldehyde-dopamine condensation product, salsolinol. The present review article aims at presenting and discussing prospectively the most recent data accumulated following these three research pathways on this never-ending story in order to offer the most up-to-date synoptic critical view on such still unresolved and exciting topic.