A Critical Review of Ethanol Effects on Neuronal Firing: A Metabolic Perspective

Overview

Journal Alcohol Clin Exp Res (Hoboken)

Specialty Psychiatry

Date 2024 Jan 12

PMID 38217065

Authors

Dina Popova

Jacquelyne Sun

Hei-Man Chow

Ronald P Hart

Affiliations

Soon will be listed here.

Abstract

Ethanol metabolism is relatively understudied in neurons, even though changes in neuronal metabolism are known to affect their activity. Recent work demonstrates that ethanol is preferentially metabolized over glucose as a source of carbon and energy, and it reprograms neurons to a state of reduced energy potential and diminished capacity to utilize glucose once ethanol is exhausted. Ethanol intake has been associated with changes in neuronal firing and specific brain activity (EEG) patterns have been linked with risk for alcohol use disorder (AUD). Furthermore, a haplotype of the inwardly rectifying potassium channel subunit, GIRK2, which plays a critical role in regulating excitability of neurons, has been linked with AUD and shown to be directly regulated by ethanol. At the same time, overexpression of GIRK2 prevents ethanol-induced metabolic changes. Based on the available evidence, we conclude that the mechanisms underlying the effects of ethanol on neuronal metabolism are a novel target for developing therapies for AUD.

References

Martinez S, Vaglenova J, Sabria J, Martinez M, Farres J, Pares X . Distribution of alcohol dehydrogenase mRNA in the rat central nervous system. Consequences for brain ethanol and retinoid metabolism. Eur J Biochem. 2001; 268(19):5045-56. View

Belanger M, Allaman I, Magistretti P . Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011; 14(6):724-38. DOI: 10.1016/j.cmet.2011.08.016. View

Hill K, Alva H, Blednov Y, Cunningham C . Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice. Psychopharmacology (Berl). 2003; 169(1):108-14. DOI: 10.1007/s00213-003-1472-4. View

Lockie S . Glucagon-like peptide-1 receptor in the brain: role in neuroendocrine control of energy metabolism and treatment target for obesity. J Neuroendocrinol. 2013; 25(7):597-604. DOI: 10.1111/jne.12039. View

Brodie M, Pesold C, Appel S . Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res. 1999; 23(11):1848-52. View

Jin M, Ande A, Kumar A, Kumar S . Regulation of cytochrome P450 2e1 expression by ethanol: role of oxidative stress-mediated pkc/jnk/sp1 pathway. Cell Death Dis. 2013; 4:e554. PMC: 3615729. DOI: 10.1038/cddis.2013.78. View

Chuong V, Farokhnia M, Khom S, Pince C, Elvig S, Vlkolinsky R . The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission. JCI Insight. 2023; 8(12). PMC: 10371247. DOI: 10.1172/jci.insight.170671. View

Hasenstaub A, Otte S, Callaway E, Sejnowski T . Metabolic cost as a unifying principle governing neuronal biophysics. Proc Natl Acad Sci U S A. 2010; 107(27):12329-34. PMC: 2901447. DOI: 10.1073/pnas.0914886107. View

Aryal P, Dvir H, Choe S, Slesinger P . A discrete alcohol pocket involved in GIRK channel activation. Nat Neurosci. 2009; 12(8):988-95. PMC: 2717173. DOI: 10.1038/nn.2358. View

10.

Abrahao K, Salinas A, Lovinger D . Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits. Neuron. 2017; 96(6):1223-1238. PMC: 6566861. DOI: 10.1016/j.neuron.2017.10.032. View

11.

Ohe T, Hirobe M, Mashino T . Novel metabolic pathway of estrone and 17beta-estradiol catalyzed by cytochrome P-450. Drug Metab Dispos. 2000; 28(2):110-2. View

12.

Simon L, Molina P . Cellular Bioenergetics: Experimental Evidence for Alcohol-induced Adaptations. Function (Oxf). 2022; 3(5):zqac039. PMC: 9469757. DOI: 10.1093/function/zqac039. View

13.

Bruser A, Kirchberger J, Kloos M, Strater N, Schoneberg T . Functional linkage of adenine nucleotide binding sites in mammalian muscle 6-phosphofructokinase. J Biol Chem. 2012; 287(21):17546-17553. PMC: 3366854. DOI: 10.1074/jbc.M112.347153. View

14.

Sisley S, Gutierrez-Aguilar R, Scott M, DAlessio D, Sandoval D, Seeley R . Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. J Clin Invest. 2014; 124(6):2456-63. PMC: 4038572. DOI: 10.1172/JCI72434. View

15.

Mews P, Egervari G, Nativio R, Sidoli S, Donahue G, Lombroso S . Alcohol metabolism contributes to brain histone acetylation. Nature. 2019; 574(7780):717-721. PMC: 6907081. DOI: 10.1038/s41586-019-1700-7. View

16.

Dettling A, Fischer F, Bohler S, Ulrichs F, Skopp G, Graw M . Ethanol elimination rates in men and women in consideration of the calculated liver weight. Alcohol. 2007; 41(6):415-20. DOI: 10.1016/j.alcohol.2007.05.003. View

17.

Shean M, Duester G . The role of alcohol dehydrogenase in retinoic acid homeostasis and fetal alcohol syndrome. Alcohol Alcohol Suppl. 1993; 2:51-6. View

18.

SenGupta T, Torgersen M, Kassahun H, Vellai T, Simonsen A, Nilsen H . Base excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy. Nat Commun. 2013; 4:2674. PMC: 3826653. DOI: 10.1038/ncomms3674. View

19.

Huang Z, Liu L, Zhang J, Conde K, Phansalkar J, Li Z . Glucose-sensing glucagon-like peptide-1 receptor neurons in the dorsomedial hypothalamus regulate glucose metabolism. Sci Adv. 2022; 8(23):eabn5345. PMC: 9177072. DOI: 10.1126/sciadv.abn5345. View

20.

Clarke T, Laucht M, Ridinger M, Wodarz N, Rietschel M, Maier W . KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking. Neuropsychopharmacology. 2011; 36(6):1142-8. PMC: 3079832. DOI: 10.1038/npp.2010.247. View