- The brain's dopamine system is particularly vulnerable to activation by addictive substa-

 New research examines the influence of brain-derived neurotrophic factor (BDNF) on the dopamine system. nces.

-- Findings indicate that variants of the BDNF gene may not only play a role in a person's committal of violence while intoxicated, but may also play a role in vulnerability to alcohol withdrawal-associated delirium tremens.

Among the many genes that may contribute to an individual's susceptibility to alcoholism, those in the dopamine system are of special interest because addictive substances can activate this system. In particular, brain-derived neurotrophic factor (BDNF) can influence both dopamine and serotonin neurotransmitters, which are heavily linked to addiction. New findings, published in the November issue of Alcoholism: Clinical & Experimental Research, suggest that variants of the BDNF gene may not only play a role in a person's committal of violence while intoxicated, but may also play a role in vulnerability to alcohol withdrawal-associated delirium tremens.

"The cell bodies of the dopamine system originate in the ventral tegmental area and send projections to the dopamine receptors in the nucleus accumbens and basal forebrain," said Sachio Matsushita, chief of psychiatry at the National Hospital Organization in Kanagawa, Japan and first author of the study. "Alcohol can activate this system. For example, alcohol consumption increases dopamine release in the nucleus accumbens from ventral tegmental neurons. Furthermore, animal studies have shown that BDNF influences both dopamine and serotonin levels." These and other results led Matsushita and his colleagues to investigate the role of BDNF in certain characteristics of alcoholics.

Alcoholic subjects consisted of 377 male Japanese inpatients who were hospitalized between January 1996 and June 1998. Researchers used structured interviews to obtain social background, drinking history, history of violence while intoxicated, history of alcohol withdrawal, and family history of alcoholism. The comparison control group consisted of 336 nonalcoholic male subjects. DNA was extracted via blood, and the G196A polymorphism (variant) of the BDNF gene was genotyped.

Results indicate that genotype and allele distributions of the BDNF gene polymorphism did not differ significantly between alcoholic and control subjects. However, comparison of clinical characteristics across G196A genotypes showed that alcoholic subjects with violent tendencies and a history of delirium tremens had a significantly higher frequency of AA genotypes and A allele frequencies than those without these characteristics.

"Our findings suggest that the BDNF gene polymorphism can modify phenotypes of alcoholism - that is, measurable and/or observable traits or behavior - and is not a mere marker," said Matsushita. "According to our study results, alcoholic patients with the A allele of the BDNF gene polymorphism might be vulnerable to delirium tremens and violence during intoxication. In other words, violent acts while intoxicated might be due to genetic factors. The BDNF gene polymorphism might also play some role in vulnerability to alcohol withdrawal delirium."

Matsushita believes these findings may not only help to understand the molecular mechanisms underlying violent behavior during intoxication as well as alcohol withdrawal delirium, but may also help to identify new treatment strategies.

"Our next plan is to confirm our results in other alcoholic populations," he said. "To confirm our results, we need to examine the relationship between the BDNF gene polymorphism and delirium tremens, violence, and onset age of alcoholism in larger, independent and/or family-based alcoholic populations."

Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Association study of brain-derived neurotrophic factor (BDNF) gene polymorphism and alcoholism," were: Mitsuru Kimura, Tomohiro Miyakawa, Toshihiro Masaki, and Susumu Higuchi of the Kurihama Alcoholism Center at the National Hospital Organization in Kanagawa; Aihide Yoshino of the Department of Psychiatry at the National Defense Medical College in Saitama; and Masanobu Murayama of the Akagi Kougen Hospital in Gunma; all located in Japan. The study was funded by the Japanese Ministry of Health, Labor and Welfare.

Contact: Sachio Matsushita, M.D.
shiguchi@wa2.so-net.ne.jp
81-46-848-1550 (Japan)
National Hospital Organization
Alcoholism: Clinical & Experimental Research