Role of the GABA Aβ2, GABA Aα6, GABA Aα1 and GABA Aγ2 receptor subunit genes cluster in drug responses and the development of alcohol dependence

Abstract

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system and it acts at the GABA A and GABA B receptors. A possible role for the GABA A receptors in alcohol action has been derived from in vitro cell models, animal studies and human research. GABA A subunit mRNA expression in cell models has suggested that the long form of the γ2 subunit is essential for ethanol enhanced potentiation of GABA A receptors, by phosphorylation of a serine contained within the extra eight amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA Aα6 and GABA Aγ2 subunits. An Arg 100/Glu 100 change at the GABA Aα6 subunit conferring altered binding efficacy of the benzodiazepine inverse agonist Ro 15–4513, was found between the AT (alcohol tolerance) and ANT (alcohol non-tolerance) rats. Several loci related to alcohol withdrawal on mouse chromosome 11 which corresponds to the region containing four GABA A subunit (β2, α6, α1 and γ2) genes on human chromosome 5q33–34, were also identified. Gene knockout studies of the role of GABA Aα6 and GABA Aγ2 subunit genes in mice have demonstrated an essential role in the modulation of other GABA A subunit expression and the efficacy of benzodiazepine binding. Absence of the GABA Aγ2 subunit gene has more severe effects with many of the mice dying shortly after birth. Disappointingly few studies have examined the effects of response to alcohol in these gene knockout mice. Human genetic association studies have suggested that the GABA Aβ2, α6, α1 and γ2 subunit genes have a role in the development of alcohol dependence, although their contributions may vary between ethnic group and phenotype. In summary, in vitro cell, animal and human genetic association studies have suggested that the GABA Aβ2, α6, α1 and γ2 subunit genes have an important role in alcohol related phenotypes (300 words).