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
"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
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
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 Psychiatry20041611776