Neurobiological Aspects of Ethanol-Derived Salsolinol

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.