A critical review of ethanol effects on neuronal firing: A metabolic perspective

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 carbons 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 found to be linked with AUD and was shown to be directly regulated by ethanol. At the same time, overexpression of GIRK2 prevents ethanol-induced metabolic changes. This review proposes that the mechanisms underlying the effects of ethanol on neuronal metabolism represent a novel target for developing therapies for AUD.

Introduction

The brain is one of the most metabolically expensive organs, consuming almost 20–25% of the body’s oxygen and glucose, while representing only 2% of the total body weight (Hasenstaub et al., 2010, Raichle and Gusnard, 2002, Belanger et al., 2011). Neuronal activity – action potential firing, input integration and synaptic transmission – accounts for up to 80% of the total energy usage in the brain (Watts et al., 2018, Hyder et al., 2013). Neurons primarily consume glucose as an energy source to produce adenosine triphosphate (ATP), which is utilized to balance metabolic the costs of electrical activity (Yi et al., 2016, Hasenstaub et al., 2010). The greatest fraction of metabolic demand supports the activity of ATP-dependent sodium-potassium pumps working to restore K⁺/Na⁺ gradients following action potential firing (Hallermann et al., 2012). Thus, there is a direct relationship between neuronal performance and metabolic status of the cells. Recent studies show that ethanol, in addition to being metabolized systemically, is metabolized preferentially as a carbon source to produce energy in neurons (Sun et al., 2023). Additionally, GIRK2, a subunit of the inwardly rectifying potassium channel, not only modulates neuronal activity, but also is itself regulated by ethanol and its overexpression affects metabolic flux (Popova et al., 2023, Prytkova et al., 2024). Our goal is to review how neuronal metabolism is altered by ethanol, causing changes in excitability and contributing to functional changes in the brain.

Considering the common usage of alcohol in society and its direct impact on brain function, relatively little is known about the role of neuronal metabolism of ethanol as an intermediate to link drinking and brain function. Others have reviewed the broad impact of ethanol on a variety of neuronal mechanisms (Abrahao et al., 2017), but recent work suggests that fundamental changes in metabolic pathways are directly linked with changes in neuronal activity. In this review, we will summarize evidence of ethanol metabolism in neurons, link metabolism with electrophysiological activity, and propose a model where metabolic modulation could be an effective therapeutic target for treatment of alcohol use and dependence.

Ethanol and neuronal metabolism

It is well known that ethanol significantly affects cellular metabolism. This has primarily been studied in liver; however, evidence supports a direct influence of ethanol on brain metabolism. Brain imaging studies have shown that acute ethanol administration transiently reduces the metabolic rate of glucose utilization, and chronic excessive alcohol intake leads to longer-lasting decreases in glucose metabolism (Volkow et al., 2017, Volkow et al., 2015). Even at low doses, with minimal behavioral effects, there is a significantly decreased baseline of brain glucose metabolism in response to ethanol (Volkow et al., 2006). Parallel to changes in glucose utilization, studies on laboratory animals and in cultured cells report reductions in ATP levels for a variety of ethanol treatment protocols including acute, chronic and binge paradigms (Simon and Molina, 2022). This supports our hypothesis that ethanol consumption leads to changes in neuronal metabolism, which in turn can affect brain function, including excitability, serving as a generalized regulator.

Ethanol metabolism in neurons.

As in the liver, ethanol metabolism in the brain involves two stages (Fig. 1A). It is first oxidized to acetaldehyde, followed by further oxidation to acetate (Zimatkin and Deitrich, 1997). While the second reaction is generally catalysed by aldehyde dehydrogenase-2 (ALDH2) located inside the mitochondria; the first reaction can utilize any of three distinct enzymes - alcohol dehydrogenase (ADH), catalase (CAT) or cytochrome P450 2E1 (CYP2E1), each located in different subcellular organelles.

Figure 1. Metabolism of ethanol in neurons.

Summary of metabolic pathways affected by ethanol utilization in neurons. See text for detailed description. A. Ethanol conversion to acetate, via CAT and CYP2E1 but reduced activity of ADH (indicated by grey text). B. Acetyl-CoA serves as input for the tricarboxylic acid (TCA) cycle. C. Reduced glucose utilization due to down-regulation of PFK1 (indicated by grey text and arrows). D. Reduced glucose uptake due to inhibition of AMPK regulation of glucose transporter expression (GLUT1,3,4). E. Pyruvate, potentially derived from astrocytic lactate, as source for multiple TCA intermediates. F. Production of glutamate (Glu) and gamma acetyl butyric acid (GABA) draws carbons from the TCA cycle, reducing NADH and, ultimately, ATP production. G. Neuronal depolarization exports potassium ions and imports sodium ions, which required energy to restore normal gradients. H. G-protein linked, inwardly rectifying potassium channel (GIRK) is a target of ethanol, affecting neuronal activity.

Class III ADH (i.e., the predominant class detected in the brain), closely resembles those targeting omega hydroxy fatty acid and therefore one possible role for this class of enzymes in the brain is the oxidation of long-chain fatty alcohols and omega hydroxy fatty acids (Giri et al., 1989). In addition, mammalian ADH (probably human Class I ADH) has also been shown to be a retinol dehydrogenase in the conversion of retinol to retinaldehyde which is then converted to retinoic acid by ALDH (Duester, 1991). Retinoic acid plays a significant role in neural tube development, therefore triggering ethanol-induced neural tube defects, in cases of fetal alcohol syndrome, possibly due to ethanol inhibition of retinol oxidation (Shean and Duester, 1993, Duester, 1994).

Catalase (CAT) is a heme-containing antioxidant enzyme which can be found in the brain. In normal physiology, CAT converts two H₂O₂ molecules to water and oxygen only at relatively high H₂O₂ levels (Nandi et al., 2019). At lower levels, catalase may act as a peroxidase and oxidize a variety of substrates. In the brain, it is responsible for the majority of acetaldehyde production from ethanol oxidation (Rhoads et al., 2012).

Cytochrome P-450 (CYP2E1) is the key enzyme of the microsomal pathway of ethanol oxidation. It is significantly expressed in different brain cell compartments, including the endoplasmic reticulum, the plasma membrane, the Golgi apparatus, as well as mitochondria (Yu et al., 2021). Brain endogenous substrates of CYP2E1 are arachidonic acids, linoleic acids, oleic acids, gluconeogenic precursors and estrogenic metabolites (Ohe et al., 2000), and xenobiotic substances (Kuban and Daniel, 2021). In the brain, CYP2E1 is involved in the oxidation of ethanol and ROS production, which can result in increased lipid peroxidation (Zimatkin et al., 2006), increased permeability of the blood-brain barrier and neurodegeneration (Jin et al., 2013).

Most brain cells are able to produce acetaldehyde via any one of these three pathways (Bowtell et al., 2007). Early immunohistochemical studies indicated that these enzymes are detected in different brain regions in both neurons and glia (Zimatkin and Deitrich, 1997, Kerr et al., 1989), with CAT- and CYP2E1-mediated reactions dominating, and the ADH reaction playing only a minor role (Zimatkin and Deitrich, 1997). While ADH can be detected immunocytochemically in brain (Buhler et al., 1983), activity studies conclude that the dominant class of enzyme in brain is the low-affinity Class III ADH, which is likely to be ineffective at ethanol concentrations found in tissues (Giri et al., 1989). Ethanol metabolized in astrocytes has been reported by others (Jin et al., 2021a, Fonseca et al., 2001), and studies have shown that astrocyte metabolism also underlies behavioral effects of ethanol (Jin et al., 2021a, Jin et al., 2021b), but we will focus here on its metabolism in neurons. Recent results from Sun and colleagues (Sun et al., 2023) agree with previous findings (Howard et al., 2003), that CYP2E1 is uniquely induced in pyramidal neurons of the prefrontal cortex upon chronic ethanol exposure.

Following ethanol oxidation, acetate, the ultimate product of this reaction, produced either locally in the brain or taken up from the circulation after release by the liver, can be readily converted to acetyl-CoA via the acetyl CoA synthetase reaction, joining the tricarboxylic cycle to produce reducing equivalents of NADH and reduced flavin adenine dinucleotide (FADH2; Fig. 1B). These can eventually produce ATP via the oxidative phosphorylation (OXPHOS) reactions (Bowtell et al., 2007), enhancing the cellular [ATP]/[ADP][Pi] energy status of many brain cells, although perhaps not to the levels attained from glucose utilization on a molar basis. Therefore, ethanol can serve as a fuel metabolite directly affecting neuronal energy homeostasis and, directly or indirectly, altering the capacity to revert to glucose utilization.

Effects on glucose uptake and glycolysis.

Among individuals who have alcohol dependence, the contribution of ethanol carbons to daily caloric intake could be as high as 50% or more (Dettling et al., 2007, Bach et al., 2019). As a negative feedback to this additional carbon input, downregulation in metabolic flux of physiological metabolites is observed, particularly the glucose metabolism in the brain (Volkow et al., 2013, Volkow et al., 2006, Volkow et al., 2015, Wang et al., 2000). The commitment step of glucose carbons into glycolysis is catalysed by phosphofructokinase-1 (PFK1) (Kanai et al., 2019), an allosteric enzyme controlled by various activators and inhibitors. The high intracellular [ATP]/[ADP] ratio — a condition immediately induced by ethanol oxidation — is known to inhibit this kinase, therefore inhibiting glycolytic flux, further reinforcing the use of ethanol-derived carbons (Fig. 1C) (Stine and Dang, 2013, Brüser et al., 2012).

A persistent high energy status will deplete intracellular [AMP] (Frost et al., 2014), which is essential to activate AMP-activated protein kinase (AMPK), a phylogenetically conserved fuel and energy-sensing enzyme that governs metabolic homeostasis (Hardie et al., 2016). Despite AMPK being a kinase which may likely regulate cellular metabolism via modulating downstream phosphorylation targets, evidence also indicates that AMPK may also control gene expression through metabolites of intermediary metabolism (Sukumaran et al., 2020). AMPK activity enhances the expression of one or more glucose transporters (GLUT1, GLUT3 and GLUT4) commonly found in the brain (Handa et al., 2000), so we speculate that diminished AMPK could reduce glucose availability (Fig. 1D), as seen in other tissues (Habegger et al., 2012). This interrupted energy supply may lead to changes in neuronal function (Volkow et al., 2015, Volkow et al., 2017), likely including excitability, and account for changes in behaviour associated with alcohol intake.

Unlike other physiological fuel metabolites like glucose, ketones and fatty acids, there is a lack of homeostatic regulation of blood ethanol levels, which renders circulating levels to approach zero within a few hours after the cessation of drinking. Due to the diminished capacity for glucose utilization caused by metabolic reprogramming, a sudden abstinence from ethanol can result in significant energy depletion in neurons or other brain cells (Volkow et al., 2015). The resulting insufficiency of energy support likely explains many withdrawal symptoms, including dysphoria, tremor, anxiety, restlessness and insomnia (Muncie et al., 2013, Wilson and Matschinsky, 2020). Of course, association of withdrawal with this type of energy depletion may be due to effects in other CNS cell types including astrocytes. Indeed, impairment of brain energy production caused by reduced glucose uptake and usage in specific areas was found to be associated with diminished cognitive and executive functions (Volkow et al., 2015, Volkow et al., 2017). Many or most of these symptoms are likely results of changes in neuronal excitability.

Effects on the TCA cycle.

As a possible compensatory response to reduced glucose utilization capacity due to chronic ethanol exposure, monocarboxylate transporters for lactate uptake are induced in neurons (Lindberg et al., 2019). Lactate is a metabolic dead-end; lactate carbons only become useful to support cellular fuel metabolism when they are converted to pyruvate via lactate dehydrogenase in the presence of cytosolic NAD⁺ (Brooks, 2020). In selected populations of neurons that express Class I alcohol dehydrogenase (ADH) (Wang et al., 2019, Martinez et al., 2001), cytosolic NAD⁺ is likely exhausted for the conversion of ethanol to acetaldehyde (Hoog and Ostberg, 2011), thereby diminishing the utilization of lactate for the astrocyte-neuron lactate shuttle (Lindberg et al., 2019). This, together with reduced glycolytic capacities, ultimately alters the neuronal lactate/pyruvate ratio (Wright and Marks, 1984).

In neurons, pyruvate is normally the starting substrate for the TCA cycle as it catabolically converts to acetyl CoA via the action of pyruvate dehydrogenase (Fig. 1E). Conversely, it can be anabolically carboxylated to form oxaloacetate (and then malate), which promotes anaplerosis through reversed TCA cycle activity (Cappel et al., 2019) to compensate for losses of α-ketoglutarate that occur through the release of the neurotransmitters glutamate and GABA (Hassel, 2001). At the co-enzyme level, continuous conversion of acetaldehyde to acetate in mitochondria exhausts mitochondrial NAD⁺ needed for driving the forward TCA cycle reactions catalysed by isocitrate, α-ketoglutarate and malate dehydrogenases. When this situation is compounded by the uncontrolled production of acetyl-CoA from acetate, the altered balance in acetyl-CoA/CoA may eventually deplete intra-mitochondrial CoA-SH required for the forward α-ketoglutarate dehydrogenase reaction, thus further diminishing the activities of the TCA cycle.

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.

Additional pathways affected by ethanol.

Other effects of ethanol metabolism include an interference with one carbon (1-C) pathways, due to a reduction in neuronal S-adenosyl methionine (Sun et al., 2023), a major methyl donor for a broad array of vital cellular processes (Bottiglieri, 2002). The intermediate in metabolizing ethanol, acetaldehyde, also induces DNA crosslinks, triggering a DNA damage response, and this has been observed in neurons (Sun et al., 2023). This is particularly dangerous since neurons are post-mitotic and therefore DNA damage induces alternate DNA repair mechanisms such as mismatch repair (MMR) leading to the recruitment of cell cycle-independent excision-based repair (Kato et al., 2017, SenGupta et al., 2013). The combination of DNA repair stimulation and 1-C pathway depletion leads to neuronal senescence (Sun et al., 2023), which likely contributes to neurodegeneration found in chronic alcohol use.

Ethanol-derived acetate may also be converted to citrate/isocitrate, which could be transported out of the mitochondria to the cytoplasm and contribute carbons to de novo lipogenesis (Lustig, 2013). Ethanol metabolism in human brain has been documented to occur with the formation of fatty acid ethyl esters. These neutral lipids can disorder membranes and interrupt mitochondrial functions (Bora and Lange, 1993). The de novo synthesized lipids may also accumulate inside neurons as oil droplets, rendering them as lipid-laden and is associated with amyloid-β peptide signals in Alzheimer’s disease patients (Gomez-Ramos and Asuncion Moran, 2007).

On the other hand, ethanol-derived acetate may convert to acetyl-CoA and promote brain histone acetylation (Mews et al., 2019). In hippocampal neurons, such epigenetic changes result in altered transcriptomic profiles to promote neuronal signal transduction, and hence the alcohol-induced associative learning and memory (Mews et al., 2019) that allows environmental stimuli paired with alcohol to acquire the ability to trigger alcohol-seeking behaviours.

Ethanol and excitability

Neuronal excitability.

Ingested alcohol, primarily in the form of ethanol, likely affects excitability of neurons, potentially through indirect effects on metabolism (Volkow et al., 2015, Volkow et al., 2017) (Fig. 1G). Slice recordings of mouse brain have revealed that acute application of ethanol enhances firing of dopamine neurons of the ventral tegmental area (VTA) (Brodie et al., 1999), lateral habenula neurons and cerebellar Golgi neurons, while decreasing the firing of VTA GABA-releasing (GABAergic) neurons (Gallegos et al., 1999), pyramidal neurons in the lateral orbitofrontal cortex (Nimitvilai-Roberts et al., 2021), and serotonergic neurons of the dorsal raphe (Maguire et al., 2014). Several studies have also reported changes in excitability following chronic exposure to ethanol. Firing was increased in mouse nucleus accumbens (NAc) medium spiny neurons recorded after long-term ethanol self-administration (Hopf et al., 2010). Similarly, repeated systemic ethanol treatment increased spontaneous action potential firing in mouse lateral habenula (LHb) neurons (Agrawal et al., 2012). Due to its amphipathic nature, ethanol can easily cross the blood brain barrier (BBB) and any cell membrane lipid bilayer (Kumari et al., 2018) directly affecting multiple molecular targets in neurons, including NMDA receptors, GABA A receptors, high-conductance Ca²⁺-activated K⁺ channel (BK channel) and G protein inwardly rectifying potassium (GIRK) channels (reviewed by Abrahao et al., 2017). Differential expression of channels, receptors and enzymes as well as the complexity of neurocircuitry can underlie discrepancies in firing responses. Overall, the link between ethanol consumption and changes in excitability is well established.

EEG responses linked with AUD.

Not only can immediate responses to ethanol affect neuronal excitability, predisposition to AUD itself has also been associated with altered excitability. Electroencephalogram (EEG) studies conducted by the Collaborative Studies on the Genetics of Alcoholism (COGA) identified neurophysiological features commonly observed among subjects diagnosed with AUD, long-term abstinent individuals, as well as individuals at risk for AUD. Multiple studies report an association between AUD and time-locked as well as resting-state EEG responses, including lower P300 amplitude in oddball tasks, lower event-related oscillation (ERO) power during reward processing, particularly frontal theta power, and increased resting state beta power (Meyers et al., 2023). This indicates a higher-level imbalance in the ratio of excitation/inhibition as an index of neural hyper excitability or disinhibition in individuals with AUD and at-risk family members, both in the presence of alcohol usage and among non-users at risk. This predicts a bi-directional interaction between altered excitability and alcohol use.

KCNJ6 expression and excitability.

An unexpected link between these EEG studies and the genetic analysis of AUD identified a haplotype of a potassium channel subunit that not only mediates changes in excitability but is also itself regulated by ethanol, with increased levels causing a shift in metabolic flux. Genome-wide association studies for one of these AUD-associated EEG phenotypes - elevated theta ERO power - have identified multiple non-coding single nucleotide polymorphisms (SNPs) within the KCNJ6 gene in strong linkage disequilibrium (LD) (Kang et al., 2012). Individuals with this haplotype of KCNJ6 SNPs demonstrated increased theta ERO power and altered EEG topography during reward processing in a monetary gambling task, suggesting a genetic influence on neuronal function (Clarke et al., 2011, Kamarajan et al., 2017). KCNJ6 encodes the G protein-coupled inwardly rectifying potassium channel subunit 2 (GIRK2), which plays a key role in controlling neuronal excitability (Glaaser and Slesinger, 2015, Luscher and Slesinger, 2010, Zhao et al., 2021). Activation of inhibitory G protein coupled receptors (GPCRs) via ligand binding leads to GIRK2 activation via Gβγ, resulting in outward potassium flux through the channel and subsequent inhibition of neuronal firing (Reuveny et al., 1994). In rodent studies, GIRK channels are implicated in alcohol-related behaviors (Blednov et al., 2001b, Blednov et al., 2001a, Hill et al., 2003, Kozell et al., 2009, Herman et al., 2015), and in humans, GIRK3 has been linked with AUD (Sanchez-Roige et al., 2019, Kozell et al., 2018), potentially through effects on GIRK2 trafficking (Ma et al., 2002). In addition, GIRK channels can be directly potentiated by alcohol through interaction with a hydrophobic pocket in the channel (Aryal et al., 2009, Bodhinathan and Slesinger, 2014).

In a recent study on induced pluripotent stem cell (iPSC)-derived glutamatergic induced human neurons, Popova and colleagues investigated molecular underpinnings of allelic variations in KCNJ6 (Popova et al., 2023). Subjects with and without a haplotype of 22 noncoding or synonymous SNP variations in KCNJ6 were selected from the COGA cell repository, chosen with the presence or absence of AUD diagnosis, respectively, to investigate the cellular, molecular and network mechanisms of these non-coding SNPs. Single-cell RNA sequencing (scRNAseq) identified multiple genes which were differentially expressed between affected and unaffected individuals. Neurons from affected individuals also had significantly lower levels of KCNJ6 mRNA expression. Fluorescence in situ hybridization (FISH) for KCNJ6 mRNA also showed a decrease, consistent with the scRNAseq results. While this conflicts with the in vivo EEG results, cultures of induced excitatory neurons in the absence of neural networks do not recapitulate the full pattern of response in brain. We found that ethanol exposure reversed these effects, demonstrating a mechanism linking ethanol with expression of a gene known to affect excitability.

At the cellular level, neurons with the variant KCNJ6 haplotype had a significantly higher density of neurites, accompanied by decreased GIRK2 levels. Physiologically, reduced GIRK2 expression was associated with increased excitability of cells generated from affected individuals both at the level of individual neurons as well as the network (Fig. 1H). Chronic ethanol treatment, however, induced both KCNJ6 mRNA and GIRK2 protein expression, ameliorating differences in neuronal excitability. Moreover, KCNJ6 overexpression alone replicated the effects of ethanol administration on neuronal excitability. These findings are not only reminiscent of the original observation linking subjects with KCNJ6 variants with increased EEG theta oscillations but also supports the hypothesis introduced by Begleiter and Porjesz (Begleiter and Porjesz, 1999), which theorized that inherited neuronal excitability can be associated with a predisposition to developing alcohol dependence.

The role of GIRK2 in regulating activity is enhanced with an unexpected link to metabolism. A recent study by Prytkova and colleagues found an intriguing interaction between ethanol treatment, neuronal excitability and metabolic performance of neurons (Prytkova et al., 2024). Overexpression of GIRK2 in iPSC-derived excitatory neurons, either by CRISPR activation (CRISPRa) or lentiviral expression, produced basal hyperpolarization of the neuronal membrane. Treatment of cultures with ethanol (17 mM for 14–21 days) enhanced firing of glutamatergic neurons but GIRK2 overexpression prevented this hyperexcitability. Finally, prolonged ethanol treatment induced metabolism-associated genes and resulted in a surge of mitochondrial respiration rates, which were reversed by overexpression of GIRK2. This study is the first to link neuronal responses to ethanol directly with changes in excitability and metabolic status of glutamatergic neurons. Taken together, these findings lead us to propose that ethanol, despite the fact it has many potential targets in neurons, may induce a generalized metabolic response, which serves as a constraint affecting key neuronal functions.

Summary and Perspective

Cellular metabolism and energy production are fundamental biochemical processes required to maintain life. Metabolic intermediates are widely used as intracellular signalling molecules affecting a host of cellular functions. Since alcohol ingestion results in systemic cellular exposure to ethanol, not only peripherally but also throughout the central nervous system, it is important to consider how ethanol can be utilized as a source of carbon and energy. In neurons, the presence of ethanol preferentially displaces glucose as catabolic input while simultaneously reducing the capacity to utilize glucose once ethanol is exhausted. This shift in energetics is predicted to degrade the capacity of neurons to replenish energy stores upon depolarization. Ethanol has been found to affect neuronal excitability. In one example of a mechanistic link between excitability and ethanol, GIRK2 levels modulate excitability and ethanol increases GIRK2 expression. Overexpression of GIRK2 abrogates both the enhanced firing of glutamatergic neurons and increased respiration rates observed following chronic ethanol treatment. This suggests a novel integration of ethanol metabolism, neuronal excitability and/or firing rates, and ion channel components that may mediate these interactions.

The long pursuit of effective therapies for AUD has produced surprisingly few successes—only three medications are currently FDA approved. Disulfiram and acamprosate help to avoid drinking and naltrexone reduces reward-associated effects, albeit with substantial side effects and with only mild effectiveness for treatment of AUD. The unexpected observation that the GLP-1 agonist semaglutide reduces alcohol consumption in rodents (Aranas et al., 2023, Chuong et al., 2023, Jerlhag, 2020) points to the re-examination of ethanol metabolism as a target of therapy. Semaglutide is believed to act primarily on receptors in the pancreas to increase circulating levels of GLP-1 although it has also been shown to stimulate GABA production by activating GAD (Wang et al., 2007) or by modulating GABA transmission (Chuong et al., 2023). Studies of GLP-1-regulated feeding behaviors have identified GLP-1 receptors in specific neurons in brain (Lockie, 2013, Sisley et al., 2014, Huang et al., 2022) including the ventral tegmental area (Alvarez et al., 2005, Merchenthaler et al., 1999). Evidence supporting its potential involvement in AUD comes largely from a genetic analysis that identified a non-synonymous SNP in GLP1R associated with AUD (Suchankova et al., 2015). The use of semaglutide to reduce alcohol consumption lacks rigorous clinical evidence, and it may rely on mechanisms outside the brain and/or utilize non-metabolic pathways. However, we speculate that it may represent a novel therapeutic strategy. With evidence that ethanol interferes with neuronal metabolism, potentially affecting excitability, and the observation that a presumed metabolic modulator reduces drinking behavior, there is ample reason to investigate this regulatory network further, with an eye towards developing therapies for those suffering from AUD.