GABAA Receptor Subtype Mechanisms and the Abuse-Related Effects of Ethanol: Genetic and Pharmacological Evidence

Abstract

Ethanol's reinforcing and subjective effects, as well as its ability to induce relapse, are powerful factors contributing to its widespread use and abuse. A significant mediator of these behavioral effects is the GABA receptor system. GABA receptors are the target for γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. Structurally, they are pentameric, transmembrane chloride ion channels comprised of subunits from at least eight different families of distinct proteins. The contribution of different GABA subunits to ethanol's diverse abuse-related effects is not clear and remains an area of research focus. This chapter details the clinical and preclinical findings supporting roles for different α, β, γ, and δ subunit-containing GABA receptors in ethanol's reinforcing, subjective/discriminative stimulus, and relapse-inducing effects. The reinforcing properties of ethanol have been studied the most systematically, and convergent preclinical evidence suggests a key role for the α5 subunit in those effects. Regarding ethanol's subjective/discriminative stimulus effects, clinical and genetic findings support a primary role for the α2 subunit, whereas preclinical evidence implicates the α5 subunit. At present, too few studies investigating ethanol relapse exist to make any solid conclusions regarding the role of specific GABA subunits in this abuse-related effect.

The neurobiology of central sensitization

“…This finding may also suggest biological plausibility for the association between low–moderate alcohol consumption (compared to none or heavy drinking), and improved symptomatology and functionality in FM (Kim et al., ; Scott et al., ). Alcohol enhances inhibitory GABAergic neurotransmission (Chandler, Overton, Ruedi‐Bettschen, & Platt, ; Chastain, ) and may exhibit a U‐shaped curve for its analgesic effects similar to its potentially beneficial cardiovascular effects. That imbalances between excitatory and inhibitory neurotransmitters are not found diffusely throughout the brain and, instead, appear to be localized to regions that contribute to multisensory processing (e.g., insula) (Brooks & Tracey, ; Craig, ), is consistent with the notion that a global sensory hyper‐responsiveness is partly responsible for the pathophysiology of FM and related COPCs (Ablin & Clauw, ; Yunus, ).…”

The endocannabinoid‐alcohol crosstalk: Recent advances on a bi‐faceted target

“…The past 2 decades of clinical research and data derived from preclinical models of alcohol addiction point to the glutamatergic and the GABAergic systems as the main target of alcohol activity in the mesocorticolimbic system, where alcohol intake results in increased dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Notwithstanding, alcohol's mechanism of action at the molecular level is fairly unknown.…”

“…Alcohol produces its effects through actions on multiple brain circuits and involves neuroadaptive changes not only in adulthood but especially in critical periods of development. 22,[25][26][27][28][29][30][31] The past 2 decades of clinical research and data derived from preclinical models of alcohol addiction point to the glutamatergic and the GABAergic systems as the main target of alcohol activity in the mesocorticolimbic system, [32][33][34][35][36][37][38] where alcohol intake results in increased dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Notwithstanding, alcohol's mechanism of action at the molecular level is fairly unknown.…”

Neuroligin Plays a Role in Ethanol-Induced Disruption of Memory and Corresponding Modulation of Glutamate Receptor Expression

“…Ethanol has been found to interact with several neurotransmitter systems. The role of GABA in mediating the intoxication effect of ethanol are well-established (see Kumar et al, 2009;Chandler et al, 2017). Glutamate has also been shown to be affected by ethanol (see Chastain, 2006;Rao et al, 2015).…”