Is There a Novel Biosynthetic Pathway in Mice That Converts Alcohol to Dopamine, Norepinephrine and Epinephrine?

Abstract

Previous studies in animals and humans have shown multiple types of interaction between alcohol (ethanol) intake and the catecholamine signaling molecules: dopamine, norepinephrine and epinephrine. This literature suggests that the administration of alcohol to rodents affects the central and peripheral (blood plasma) levels of these catecholamines. Two prior publications (Fitzgerald 2012, 2020) put forth the hypothesis that there may be a currently unidentified biosynthetic pathway, in a range of organisms, that actually converts alcohol to dopamine, norepinephrine and epinephrine. This publication describes the details for how to test this hypothesis in mice. Mice can be systemically injected with an intoxicating dose of commercially available stable isotope-labeled ethanol (ethanol-1-¹³C), and blood plasma samples and brains can be collected approximately two to 24 h post-injection. Liquid chromatography-mass spectrometry analysis can then be used to test whether some of the labeled ethanol molecules have been incorporated into new dopamine, norepinephrine, and epinephrine molecules, in plasma and brain samples. If confirmed, this hypothesis may have broadly reaching implications both for basic neuroscience and our understanding of alcohol abuse and alcoholism.

Keywords: addiction; catecholamines; dependence; ethanol; reward; substance abuse.

Figure 1

Canonical pathway for the endogenous synthesis of catecholamines and possible additional pathways involving ethanol. This pathway was described over 70 years ago, and posits that there is a single, principal biosynthetic pathway in mammals that converts the amino acid tyrosine to dopamine (via L-DOPA), and subsequently to norepinephrine and epinephrine (A). The middle portion of the figure (B) shows the structure of C12 unlabeled ethanol (left) and the C13 labeled ethanol (right) proposed to be used here. The * indicates where the C13 is located within the molecule. (C) Various plant-derived phenylic molecules that may combine with ethanol in vivo to produce catecholamines. Yellow boxes highlight an ethanol-like moiety already present within the flavonoids quercetin and catechin, that could lead to biotransformation to catecholamines even in the absence of ethanol.