Ethanol Metabolism and Acetic Acid Production in the Mesolimbic Pathway is Brain Region Specific and Sex-Dependent
Ethanol is a commonly used and misused substance. Upon consumption, ethanol is first metabolized to acetaldehyde, followed by a rapid conversion to acetic acid/acetate. The literature demonstrates a tendency for females to metabolize and display a higher sensitivity to ethanol than their male counterparts. Recent work out of our labs has identified that via an N-methyl-D-aspartate (NMDA) receptor mechanism, physiologically relevant concentrations of the ethanol metabolite, acetic acid, produce rapid, excitatory modulation of neurons in the nucleus accumbens shell (a critical node in reward circuitry). How this factors into sex differences in the acquisition and progression of alcohol use disorder (AUD) is a key question. Thus, we set out to better understand the effects of acetic acid on the mesolimbic reward pathway. Using ion chromatography, we quantified acetic acid concentrations produced after acute ethanol exposure in two key areas implicated in ethanol seeking, the nucleus accumbens (NAc) and ventral tegmental area (VTA). We observed sex-dependent metabolic profiles in both the NAc and VTA. Furthermore, in situ hybridization experiments targeting the NAc and VTA of ethanol naïve animals demonstrated baseline sex differences in mRNA expression for the NR1 subunit of the NMDA receptor, monocarboxylate transporter 2 (SLC16A7), and aldehyde dehydrogenase (ALDH2), key proteins in the generation, sequestration, and mechanisms of action of acetic acid. These findings suggest there are brain region and sex-specific differences in acetic acid production/sequestration that may underlie the neurophysiological effects of ethanol in a sex-dependent manner.