Role of the GABA(A)beta 2, GABA(A)alpha 6, GABA(A)alpha 1 and GABA(A)gamma2 receptor subunit genes cluster in drug responses and the development of alcohol dependence

gamma-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 deri ved from in vitro cell models, animal studies and human research. GABA(A) s ubunit mRNA expression in cell models has suggested that the long form of t he gamma 2 subunit is essential for ethanol enhanced potentiation of GABA(A ) receptors, by phosphorylation of a serine contained within the extra eigh t amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA(A)alpha 6 and GABA(A)gamma 2 subunits. An Arg(100)/Glu(100) change at the GABA(A)alpha 6 subunit conferring altered binding efficacy of the benzo diazepine inverse agonist Ro 15-4513, was found between the AT (alcohol tol erance) and ANT (alcohol non-tolerance) rats. Several loci related to alcoh ol withdrawal on mouse chromosome 11 which corresponds to the region contai ning four GABA(A) subunit (beta 2, alpha 6, alpha 1 and gamma 2) genes on h uman chromosome 5q33-34, were also identified. Gene knockout studies of the role of GABA(A)alpha 6 and GABA(A)gamma 2 subnnit genes in mice have demon strated an essential role in the modulation of other GABA(A) subunit expres sion and the efficacy of benzodiazepine binding. Absence of the GABA(A)gamm a 2 subunit gene has more severe effects with many of the mice dying shortl y after birth. Disappointingly few studies have examined the effects of res ponse to alcohol in these gene knockout mice. Human genetic association stu dies have suggested that the GABA(A)beta 2, alpha 6, alpha 1 and gamma 2 su bunit 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 suggeste d that the GABA(A)beta 2, alpha 6, alpha 1 and gamma 2 subunit genes have a n important role in alcohol related phenotypes (300 words). (C) 2000 Elsevi er Science Ltd. All rights reserved.