Excitatory neurons may be selectively affected by ethanol through these mechanisms. Since glutamate is a direct derivative of α-ketoglutarate, it can be consumed in the TCA cycle to bypass the roadblocks set by the NAD+-dependent isocitrate dehydrogenase (Fig. 1F). Previous studies on the effect of acetate infusion in a live mouse model revealed reduced rates of TCA and the neurotransmitter cycle associated with glutamatergic and GABAergic neurons in cortical and subcortical regions, resulting in reduced excitability and inhibitory activities differentially across the regions of the brain (Tiwari et al., 2014). Moreover, extracellular glutamate levels in the synaptic regions become aberrantly reduced due to increased ATP-dependent uptake activity and endocytosis of neurotransmitters. Together, these may contribute to the sedative effect of ethanol via reducing glutamatergic (excitatory) neural activity.
