The role of GABA(A) 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.

FIGURE 1. Chromosomal clusters for GABA_A receptor genes in the HapMap Caucasian population

Arrows indicate gene position, size and direction of transcription. Red triangles show areas of linkage disequilibrium with D’ ≥ 0.8. Conservation (vertical lines) across 17 vertebrate species, from zebrafish to humans is show across the chromosomal regions.

FIGURE 2. GABRA2 gene structure

The large arrow indicates the direction of transcription. CDS = coding sequence are shown, linked by dotted lines to the relevant exons. TM domains = transmembrane domains, numbering 1 through 4 from left to right. The locations of the TM domains within the coding sequences are shown. HapMap population blocks are indicated: CEU = Caucasian; ANS = Asian; YRI = African. The structure of 12 isoforms is shown. Conservation across 17 vertebrate species, from zebrafish to humans is indicated. Information derived from HapMap and the UCSC genome browser: www.genome.ucsc.edu

FIGURE 3. GABRA2 common haplotypes for HapMap Asian, African and Caucasian samples

Black lines indicate the genotyped SNPs; the two colors indicate the two alleles for each SNP. All 3 populations show 2 haplotype blocks with the block boundary in intron 3. The Asian and Caucasian populations both have 2 common haplotypes in the distal haplotype block. The Africans show more haplotype diversity.