Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

Abstract

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.

Keywords: acetaldehyde; dopamine; epigenetics; ethanol; ethanol metabolism; mesolimbic system; neuroinflammation; salsolinol.

Figure 1

Schematic representation of hepatic metabolism of ethanol. The figure depicts, in the liver, the sub-cellular (cytosolic, peroxisomal and mitochondrial) localization of the main pathways of ethanol oxidative metabolism to acetaldehyde and of the main pathways of ethanol by-products (acetaldehyde and acetate) disposal, with indication of the relative co-factors involved. Abbreviations: ADH, Alcohol dehydrogenase; ALDH, Aldehyde dehydrogenase; ATP, adenosine triphosphate; CYP2E1, isoform 2E1 of cytochrome P₄₅₀; FADH₂, flavin-adenine dinucleotide coenzyme in its reduced form; NAD⁺, nicotinamide adenine dinucleotide coenzyme; NADPH, Nicotinamide Adenine Dinucleotide Phosphate coenzyme in its reduced form.

Figure 2

Schematic representation of central metabolism of ethanol. The figure depicts the three main central metabolic pathways of ethanol oxidative metabolism to acetaldehyde and the main metabolic pathways of ethanol by-product (acetaldehyde and acetate) disposal, with indication of the relative co-factors involved. Abbreviations: ADH, Alcohol dehydrogenase; ALDH, Aldehyde dehydrogenase; ATP, adenosine triphosphate; CYP2E1, isoform 2E1 of cytochrome P₄₅₀; FADH₂, flavin-adenine dinucleotide in its reduced form; H₂O₂, Hydrogen peroxide; NAD⁺, nicotinamide adenine dinucleotide coenzyme; NADPH, Nicotinamide Adenine Dinucleotide Phosphate coenzyme in its reduced form.

Figure 3

Opposite responses elicited by ethanol and its derivatives on the activity of mesolimbic dopaminergic system. Simplified schematic representation of the effects of ethanol metabolites on pVTA DA neurons. Ethanol evokes an inhibition of pVTA DA neurons through presynaptic (Weiner and Valenzuela, 2006) and postsynaptic GABAergic mechanisms. On the other hand, salsolinol induces an excitation of pVTA DA neurons through MOP receptors activation located in the soma and terminals of GABA neurons. Abbreviations: DA, dopamine. GABA, γ-aminobutiric acid. GABA_A, GABA receptors type A. μ, MOP receptors.