Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations

Abstract

Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we used an indirect approach, measuring the effect of alcohol on metabolism of [3-13C]pyruvate in the adult Guinea pig brain cortical tissue slice and comparing the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-13C]ethanol. Ethanol (10, 30 and 60 mM) significantly reduced metabolic flux into all measured isotopomers and reduced all metabolic pool sizes. The metabolic profiles of these three concentrations of ethanol were similar and clustered with that of the α4β3δ positive allosteric modulator DS2 (4-Chloro-N-[2-(2-thienyl)imidazo[1,2a]-pyridin-3-yl]benzamide). Ethanol at a very low concentration (0.1 mM) produced a metabolic profile which clustered with those from inhibitors of GABA uptake, and ligands showing affinity for α5, and to a lesser extent, α1-containing GABA(A)R. There was no measureable metabolism of [1,2-13C]ethanol with no significant incorporation of 13C from [1,2-13C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabeled ethanol. The reduction in metabolism seen in the presence of ethanol is therefore likely to be due to its actions at neurotransmitter receptors, particularly α4β3δ receptors, and not because ethanol is substituting as a substrate or because of the effects of ethanol catabolites acetaldehyde or acetate. We suggest that the stimulatory effects of very low concentrations of ethanol are due to release of GABA via GAT1 and the subsequent interaction of this GABA with local α5-containing, and to a lesser extent, α1-containing GABA(A)R.

Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation

“…The doses of ethanol used in this experiment were high (0.38–3%, equivalent to 64–512mM). However, considering that concentrations of alcohol in the blood, brain, and upper gastrointestinal tract can reach 100, 200, and 3400mM, respectively, following binge drinking (22, 54, 55), and that none of our employed doses induced measureable cell death (Figure 1B), we feel that our chosen doses have physiologic relevance.…”

Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling

“…The first model contained data from a range of experiments using ligands active in the glutamatergic system (for list of ligands and experiments, see Appendix S1). The second model contained data from a range of experiments using ligands active in the GABAergic system (Nasrallah et al 2007(Nasrallah et al , 2010a(Nasrallah et al ,b, 2011Rae et al 2009Rae et al , 2014Rae et al , 2015.…”

Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism

“…Brain cortical tissue slices were prepared as described elsewhere (Bröer et al, ; Nasrallah et al, ; Rae et al, ). After metabolic recovery, slices were incubated for 1 hr with [3‐ 13 C]pyruvate (control) and with either 46 or 130 μM resveratrol (SIRT 1 activator; Gertz et al, ), either 0.16 or 16 μM SRT1720 (SIRT1 activator; Milne et al, ), or 100 nM EX‐527 (SIRT1 inhibitor; Napper et al, ).…”