Alcohol is a widely used substance worldwide. While its effects on health remain unclear at low doses, several studies report that alcohol abstinence improves health, including sleep [1]. However, its consumption increases the risk of certain types of cancers, heart disease, and stroke [2]. Chronic alcohol consumption in high doses leads to cognitive impairments and dysphoria while increasing the risk of developing an alcohol use disorder (AUD), a condition characterized by a problematic pattern of alcohol use that leads to significant impairment or distress [3]. Ethanol, the psychoactive component in alcohol, induces anxiolysis and disinhibition [4] through its interaction with key neurotransmitter systems, including the delicate balance between gamma-aminobutyric acid (GABA) and glutamate.
While glutamate is the major excitatory neurotransmitter, GABA is the principal inhibitory neurotransmitter of the brain [5,6]. GABA plays an essential role in balancing neuronal excitatory and inhibitory activity. It binds to two types of receptors: ionotropic (GABA-A and GABA-C) and metabotropic (GABA-B) receptors [7]. Activation of ionotropic receptors triggers the opening of chloride ion channels in the neural membrane. The following influx of chloride ions hyperpolarizes the neuron, reducing its excitability by decreasing its chances of getting activated by an action potential. In contrast, GABA-B receptors modulate ion channels, neurotransmitter release, and membrane potentials, allowing a fine-tuning of the neuron activity in the brain [8].
Alcohol triggers neurological changes by altering the GABAergic and glutamatergic systems
While short-term exposure to alcohol temporarily alters the balance between neuronal excitatory and inhibitory activity, long-term exposure disrupts neurochemical homeostasis. As a result, the brain chemically adapts to restore equilibrium, triggering neurological changes in which ethanol becomes an integral component of neuronal function [5,9]. This brain adaptation leads to an increased tolerance to alcohol’s effects and dependence [10]. When alcohol consumption is reduced or discontinued, the absence of its effects on neurotransmission results in alcohol withdrawal syndrome (AWS), driven by the elevated activity of neurotransmitter systems [11].
Ethanol principally alters the inhibitory GABA pathway. Indeed, its primary targets, inducing disinhibition, hyperlocomotion, and anxiolysis, are GABA-A receptors. Additionally, ethanol binds to GABA-B receptors [12,13]. The extent of GABA signaling dysregulation is influenced by both the intensity and duration of alcohol consumption. Ethanol also directly binds to and inhibits N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamatergic receptors [14]. Via GABAergic and glutamatergic neurons or their respective receptors on other neuron types, ethanol induces a cascade of events leading to dopamine, serotonin, and endogenous opioid release [15,16].
Effects of a single dose of alcohol on GABA signaling
In animal models, acute ethanol at high doses alters the expression and trafficking of GABA-A receptors [17]. GABA-A receptors are pentameric assemblies from a selection of 19 possible subunits: six α (α 1-6), three β (β 1-3), three γ (γ 1-3), three ρ (ρ 1-3), and one each of the δ, ε, π, and θ subunits [18]. Combinations of these 19 subunits produce numerous receptor isoforms, each with unique localization patterns and distinct physiological and pharmacological properties. Ethanol induces transient plastic changes in GABA-A receptor subunit composition and regional and subcellular localization [19]. An intraperitoneal injection of ethanol in rats triggers the downregulation of extrasynaptic α4βδ–GABA-A receptors (located outside synapses on the neuronal membrane) in the hippocampus within 15 minutes, while GABA-A receptors containing α4, β3, and δ subunits internalize, accompanied by increased β3 phosphorylation. After several hours, α1βγ2–GABA-A receptors are down-regulated [20,21]. And after two days, α4βγ2–GABA-A receptors are up-regulated [20]. These transient changes are reversible; however, GABA-A receptors only recover two weeks after acute ethanol exposure [22].
Effects of social drinking on GABA signaling
In rats, voluntary ethanol consumption increases dopamine in the mesolimbic reward pathway [23], a pathway associated with addiction [24]. It also increases α4/δ GABA-A receptors, which are highly responsive to ethanol even at lower concentrations [25], in the hippocampus of socially isolated mice and rats [26,27]. Consequently, with each episode of social drinking, ethanol targets and stimulates extrasynaptic GABA-A receptors and triggers changes in their dynamics, setting the stage for longer-term adaptations that underlie chronic alcohol use. Studies in knockout and deficient mice suggest the involvement of GABA-A receptors (via their α5 and δ subunits) in regulating drinking behavior [28-30].
Effects of chronic alcohol consumption on GABA signaling
While animal models cannot fully replicate the complexity of human alcohol dependence and withdrawal syndrome seen in AUD, chronic intermittent ethanol gavage in rats produces remarkably comparable behaviors, including anxiety, increased seizure susceptibility, and tolerance to alcohol [31,32]. These behaviors are primarily caused by changes in GABA-A receptors after chronic exposure to ethanol, such as significantly increased α4 and reduced postsynaptic α1-containing GABA-A receptors [32–35]. Interestingly, the α4 subunit is involved in mood changes and anxiety [36], while the α1 subunit is involved in sedation and anterograde amnesia [37].
Effects of alcohol withdrawal on GABA signaling
Following alcohol withdrawal, the downregulation of GABA-A receptors, combined with the restoration of NMDA receptor activity, significantly contributes to the symptoms of alcohol withdrawal syndrome (AWS) [38,39]. Downregulation of GABA-A receptors may contribute to the anxiety and seizures of withdrawal. Dysfunctional dopaminergic transmission [40] may be responsible for hallucinations. Finally, in rats, alcohol withdrawal significantly reduces dopamine and serotonin in the reward neurocircuitry [41-43], which is commonly associated with dysphoria, depression, and anxiety disorders [44,45].
GABA-A and GABA-B receptors as therapeutic targets for the treatment of AUD
The GABAergic system is involved in the development of AUD. The activation of central GABAergic neurotransmission is associated with mesolimbic dopaminergic activity during reward-related processes, which plays a role in alcohol addiction [45-47]. Therefore, GABA receptors are potential therapeutic targets for the treatment of AUD [22]. Several allosteric modulators targeting GABA-A and GABA-B receptors showed promising results for the treatment of AUD, including negative allosteric modulators of α5-containing GABA-A receptors, positive allosteric modulators of α4/6δ GABA-A receptors, and positive allosteric modulators of GABA-B receptors [48,49].
Conclusion
Alcohol consumption disrupts GABAergic and glutamatergic signaling, leading to both immediate and long-term neuroadaptive changes that drive AUD and AWS. These mechanisms, including changes in GABA-A receptor dynamics and disruptions in the balance between excitatory and inhibitory neurotransmission, underscore the complexity of alcohol's effects on the brain. The GABAergic system is the primary target of ethanol, acting through its GABA-A and GABA-B receptors, and plays a key role in AUD. Therefore, allosteric modulators of both receptor types represent promising therapeutic avenues for addressing AUD, offering potential benefits in reducing dependence, alleviating AWS, and restoring neurochemical balance.
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