The role of GABAA receptors in the development of alcoholism

Abstract

Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

Alcohol-Responsive Writer's Cramp

“…Alcohol can induce the GABAA receptor plasticity. GABAA receptors modulate anxiety and response to stress; thereafter alcohol possibly lead to decrease level of anxiety and may promote clinical improvement of the disease (11,12). Similar responses to alcohol have also been described in primary writing tremors (13).…”

“…In addition to the direct effects of alcohol on the basal ganglia and associated structures, we cannot rule out the possibility that the anxiolytic influence or placebo effect of alcohol may contribute to its beneficial effects on the disease. There have been several reports on the anxiolytic effects of alcohol consumption (11,12). Alcohol can induce the GABAA receptor plasticity.…”

Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk

“…Within the haplotype block showing these associations, there are two common yin-yang haplotypes that account for the majority of the diversity in Caucasians (Enoch, 2008). The less frequent haplotype has been associated with alcoholics without comorbid drug dependence (Covault et al, 2004) and those with a family history of alcoholism (Fehr et al, 2006).…”

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

“…In the mature brain, chronic intermittent EtOH (CIE) administration leads to persistent alterations in GABA A R subunit composition, localization, and function, reviewed in [13,18]. GABA A R plasticity is an important underlying mechanism of alcohol withdrawal symptoms, such as anxiety, hyperexcitability and tolerance to alcohol, as well as alcohol dependence [19][20][21]. By contrast, FAE effects on GABA A Rs are not well understood, in part because GABA A R subunit composition and function is highly developmentally regulated, with many subunit combinations expressed only postnatally [22,23].…”