Production of the Short Chain Fatty Acid, Acetic Acid/Acetate from Ethanol Metabolism Activates NMDAR

Short chain fatty acid (SCFA) regulation of neuronal function remains an interesting but poorly understood area of research. The SCFA, acetic acid, the main component of vinegar and the major metabolite of ethanol has been directly linked to altering neuronal function. However, the underlying mechanisms as it relates to alcohol consumption and SCFA regulation of neuronal function have yet to be elucidated. Here we show that local metabolism of ethanol to acetic acid/acetate in the central nucleus of amygdala (CeA) activates glutamatergic N-methyl-D-aspartate receptors (NMDAR) in vivo causing a sympathoexcitatory response. External acetate and intracellular loading of acetic acid in CeA neurons increased neuronal excitability through activation of NMDAR. Furthermore, cultured neurons exposed to acetate showed increased cytosolic calcium which response was abolished by NMDAR antagonist and decreased pH. These findings suggest that acetic acid/acetate is an underestimated bioactive metabolite of ethanol that mediates some effects via an NMDAR-dependent mechanism in the brain. The link between the SCFA, acetic acid/acetate on increased neuronal excitability at least partially through NMDAR may provide a novel avenue for understanding alcohol, metabolic, cardiovascular and neurodegenerative disorders related to alterations in SCFA concentrations in the brain.