TY - JOUR
T1 - Role of the GABA(A)β2, GABA(A)α6, GABA(A)α1 and GABA(A)γ2 receptor subunit genes cluster in drug responses and the development of alcohol dependence
AU - Loh, El Wui
AU - Ball, David
N1 - Funding Information:
The work of El-Wui Loh was supported by several funding bodies. The Psychiatry Research Trust and the Peacock Foundation in the UK funded El-Wui Loh between 1996–1999. Part of the funds was provided by the Department of Health (grant no.: DOH89-TD-1094) and the National Science Council (grant no.: NSC-89-2314-B-109-003), Taiwan. We are grateful to Mr. Steven Chen, the Centec Scientific Inc, Taipei, Taiwan, for his kindness to provide a notebook computer for documentation. We also wish to thank Professor Robin Murray, the head of Department of Psychological Medicine, Institute of Psychiatry.
PY - 2000/11/1
Y1 - 2000/11/1
N2 - 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(A)α6 and GABA(A)γ2 subunits. An Arg100/Glu100 change at the GABA(A)α6 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(A)α6 and GABA(A)γ2 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(A)γ2 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(A)β2, 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(A)β2, α6, α1 and γ2 subunit genes have an important role in alcohol related phenotypes (300 words). Copyright (C) 2000 Elsevier Science Ltd.
AB - 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(A)α6 and GABA(A)γ2 subunits. An Arg100/Glu100 change at the GABA(A)α6 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(A)α6 and GABA(A)γ2 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(A)γ2 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(A)β2, 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(A)β2, α6, α1 and γ2 subunit genes have an important role in alcohol related phenotypes (300 words). Copyright (C) 2000 Elsevier Science Ltd.
KW - Alcohol
KW - Benzodiazepines
KW - Chromosome 5q33-34
KW - GABA(A)
KW - Genetic polymorphisms
KW - Receptor subunit
UR - http://www.scopus.com/inward/record.url?scp=0034310739&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034310739&partnerID=8YFLogxK
U2 - 10.1016/S0197-0186(00)00054-1
DO - 10.1016/S0197-0186(00)00054-1
M3 - Article
C2 - 10871693
AN - SCOPUS:0034310739
SN - 0197-0186
VL - 37
SP - 413
EP - 423
JO - Neurochemistry International
JF - Neurochemistry International
IS - 5-6
ER -