Brain-Receptor Abnormality Linked to Alcoholism Risk

Although alcohol is the most widely used drug of abuse, it is only slowly giving up the secrets of how it causes addiction in the brain.

For instance, particular regions of the prefrontal cortex and thalamus have been found to “light up” when an alcoholic patient views pictures of alcoholic beverages (Psychiatric News, July 6, 2001). The brain's endogenous opioid system also appears to be involved in alcoholism. And now it appears that altered nerve receptors for the neurotransmitter glutamate contribute to the development of the disorder, a study reported in the October American Journal of Psychiatry suggests.

Specifically, a family history of alcoholism is a well-known risk factor for the development of alcohol dependence. Also, NMDA receptors for glutamate are known to be among the main targets of alcohol in the brain. So Ismene Petrakis, M.D., director of the Substance Abuse Treatment Program at VA Connecticut Healthcare System, and colleagues suspected that an inherited abnormality in NMDA receptors might be involved in alcohol dependence.

The researchers gave 29 healthy young adults with no family history of alcohol dependence and 16 healthy young adults with such a history 40-minute intravenous infusions of saline, low-dose ketamine, and high-dose ketamine on three separate days under double-blind conditions. Ketamine is an antagonist of NMDA receptors and produces effects similar to those of alcohol.

The researchers then compared responses of the two groups.

In both groups ketamine produced effects similar to alcohol such as euphoria and sedation. And both groups experienced similar “highs” and drowsiness from it. However, the group with a family history of alcohol dependence incurred significantly less dysphoria—that is, anxiety, depressive mood, somatic concern, and guilt feelings—in response to ketamine and significantly fewer negative symptoms such as emotional withdrawal and psychomotor retardation in response to ketamine than did the group without a history of alcohol dependence.

The researchers thus believe that persons with a family history of alcohol dependence inherit altered NMDA receptors, and such altered receptors then play a role in alcohol dependence, especially since other studies have shown that a reduced sensitivity to the dysphoric effects of alcohol is the strongest predictor of the subsequent development of alcoholism.

In short, people who have inherited altered NMDA receptors may lack the warning signs to stop drinking after they have consumed moderate amounts of alcohol.

“This study,” Petrakis said in a Psychiatric News interview, “is important in understanding one potential neurobiological mechanism for the development of alcohol dependence, where `at risk' individuals may not experience the negative consequences of alcohol consumption (the `brakes'), which, in combination with certain circumstances, may lead to repeated bouts of excessive alcohol use. Education for individuals who are `at risk' (which is unfortunately still only loosely defined as those with a strong family history—one day genetic testing may be relevant) or for concerned parents of children at risk may alert them that they will need other... cues to regulate their drinking before it becomes a serious problem.”

These findings constitute “an important clue in the search for biological factors that increase the vulnerability for alcoholism,” Charles O'Brien, M.D., Ph.D., a professor of psychiatry at the University of Pennsylvania, said in an editorial accompanying the study report.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism and by the Department of Veterans Affairs VA-Yale Alcohol Research Center.

The study, “Altered NMDA Glutamate Receptor Antagonist Response in Individuals With a Family Vulnerability to Alcoholism,” is posted online at<http://ajp.psychiatryonline.org/cgi/content/full/161/10/1776>.▪

Am J Psychiatry 2004 161 1776