Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the human central nervous system. Previous research has suggested that GABA is involved in many of the neurochemical pathways affecting alcohol use, abuse and dependence. A study in the January issue of Alcoholism: Clinical & Experimental Research, using family-based analyses to examine the role of a cluster of GABAA receptor genes on chromosome 15q, becomes one of the first to demonstrate a consistent association between alcohol dependence and GABAA receptor gene GABRG3.
"There are several lines of evidence that suggest that GABA is involved in alcohol use and abuse," explained Danielle M. Dick, assistant professor in the department of psychiatry at Washington University School of Medicine and first author of the study. "For example, chemicals that increase the activity of GABAA receptors tend to accentuate the behavioral effects of alcohol, such as motor incoordination, sedation, and withdrawal signs, while chemicals that block GABAA receptors lessen these effects."
For this study, Dick and her colleagues decided to focus on GABAA receptor genes on chromosome 15q because of earlier findings from the multi-site Collaborative Study on the Genetics of Alcoholism (COGA) "suggesting a gene influencing alcoholism-related phenotypes in this area," she said.
Tapping into the COGA data once again, researchers tested for an association between alcohol dependence and three chromosome 15q GABAA receptor genes – GABRA5, GABRB3, and GABRG3 – in 2,282 individuals from 262 alcoholic families.
Results indicate a consistent association between alcohol dependence and one of the chromosome 15q GABAA receptor genes: GABRG3.
"Our results suggest that this gene plays a role in influencing the risk for alcoholism," said Dick. Furthermore, she added, this finding supports the theory that a predisposition to alcoholism may be inherited as a general state of central nervous system ‘disinhibition’ or hyperexcitability, in that alcohol alleviates the hyperexcitability, providing a normalizing effect.
"It is likely that many genes that influence alcoholism act through indirect pathways," said Dick, "in other words, there is no gene that directly causes you to become alcoholic, but rather there are genes that alter your risk of becoming alcoholic. Accordingly, people don’t inherit ‘alcoholism,’ per se, but rather, some people inherit a genetic makeup that puts them at risk for developing alcoholism. This is called a ‘predisposition.’ It has been theorized that the predisposition for alcoholism may be a brain state in which the brain circuits are overactive. Alcohol may have the effect of returning the brain to a more normal state. Accordingly, people with this inherited overactivity are more likely to drink in order to return to the normalized state, and this puts them at increased risk of developing alcoholism."
However, she cautions, findings thus far only suggest a potential relationship between the GABA genes on chromosome 15 and the risk for alcoholism. "Until this relationship is more clearly understood," she said, "through studies of brain cells, for example, it will not be possible to directly apply this new knowledge toward education, prevention, intervention, or treatment. The next step is to try to identify the specific genetic variation that influences alcohol dependence. Identification of these variants and further studies of their biological role in brain cells should lead to greater understanding of how these genes act in relevant biochemical pathways and thereby influence the risk for alcoholism."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Dick, D.M., Edenberg, H.J., Xuei, X., Goate, A., Kuperman, S., Schuckit, M., Crowe, R., Smith, T.L., Porjesz, B., Begleiter, H., Foroud, T. (January 2004). Association of GABRG3 with alcohol dependence. Alcoholism: Clinical & Experimental Research, 28(1), 4-10.