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The glutamate decarboxylase 1 gene may play a pivotal role in developing alcoholism

October 25, 2006

GAD1 may also play a significant role in the outcome of alcohol withdrawal

- Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain.

- An enzyme called glutamate decarboxylase (GAD) is involved in the synthesis of GABA.

- Results indicate that the GAD1 gene may play a role in the development of alcoholism as well as the outcome of alcohol withdrawal.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA has been implicated in the development of alcoholism, although the mechanisms through which this occurs are unclear. A recent "association" study has found that an enzyme called glutamate decarboxylase (GAD) - which is involved in the synthesis of GABA - may play a significant role.

Results are published in the November issue of Alcoholism: Clinical & Experimental Research.

"GABA's main function is to inhibit excitatory neuro-activities so that the brain can remain stable," said Andrew T.A. Cheng, Distinguished Research Fellow and professor at Academia Sinica in Taipei. "When one consumes alcohol, GABA levels rise in the brain, providing sedative effects. When one drinks regularly, a counter mechanism is set up until gradually, the ability to raise GABA is reduced. Defects in GABA synthesis may push one to drink more alcohol in order to treat abnormal physiology caused by low GABA Furthermore, individuals who release GABA slowly during alcohol consumption may consume more alcohol to reach its sedative effects, exposing themselves to a higher risk of alcohol dependence." Cheng is also the corresponding author for the study.

"This study takes a so-called candidate gene approach to explore the possible role of GABA in the development of alcoholism," observed Wei-Jen Chen, director of the Institute of Epidemiology at the National Taiwan University Hospital. "GAD has two forms, encoded by the GAD1 and GAD2 genes that are located in different chromosomes, and is involved in the production of GABA from glutamate. This knowledge is mainly derived from studies on mice, whereas human studies so far point to the potential role of GAD in schizophrenia."

Researchers examined two groups of Han Taiwanese men recruited from community and clinical settings: 140 who met Diagnostic and Statistical Manual-III-R criteria for alcohol dependence (22 to 69 years of age); and 146 individuals without alcohol dependence (41 to 84 years of age).

"This is the first study reporting a significant association of the GAD1 gene with the development of alcoholism," said Cheng. "Because GAD1 is the major enzyme in the synthesis of GABA, GAD1 may act as a common factor in the development of common diseases across populations, including alcoholism."

"Although statistical analyses seem to indicate that certain genetic variants of the GAD1 gene were associated with alcohol dependence," added Chen, "the meaning of this association remains to be clarified. For example, one may guess that these genetic variants are probably merely markers that are closely located to a 'real' susceptibility gene for alcohol dependence and hence form 'linkage disequilibrium' with it. Nonetheless, this study does remind researchers that GAD might be involved in maintenance of GABA levels. People with a lower GABA level that is attributed to a less active form of GAD may have a greater chance to drink alcohol to help augment the effects of the inhibitory neurotransmission exerted by GABA. This may also help explain co-occurring anxiety disorders in people with alcohol dependence."

For example, said Chen, patients with schizophrenia are known to have an increased co-occurrence of substance use disorders. Given that the GAD gene has been implicated in genetic susceptibility to schizophrenia too "it might be that the GAD gene confers a common liability to both alcohol dependence and schizophrenia," he said, "probably via the dysfunction of the GABA-related neurotransmission."

Nonetheless, said Cheng, "in order to become an alcoholic, one must be exposed to alcohol first. An individual's genetic background may play a role in pushing someone to become an alcoholic by creating physical and psychological memories that lead to a further demand for alcohol. Our findings may provide a scientific basis to further explore GABA involvement in the development of alcoholism. Advances in this field are likely to create new treatment strategies in alcoholism, either by modern molecular intervention, traditional chemical therapeutics, or psychological approaches based on a GABA-deficit theory."

Alcoholism: Clinical & Experimental Research