"This is an intriguing finding," notes NIAAA Director Ting-Kai Li, M.D. "These experiments, conducted in rats selectively bred to have a high affinity for alcohol, help us address questions about the potential role that anxiety might play in human alcoholism. These molecular studies also may reveal potential targets for therapy of anxiety and alcoholism."
Some researchers have suggested that high levels of anxiety may predispose some individuals to becoming alcoholic.
Researchers led by Subhash C. Pandey, Ph.D., Associate Professor and director of neuroscience alcoholism research in the Department of Psychiatry at the University of Illinois and Jesse Brown VA Medical Center in Chicago, found that "P" rats, a strain bred to prefer alcohol, showed more anxiety-like behaviors and drank more alcohol, than non alcohol-preferring "NP" rats. They measured anxiety in the rats with an apparatus known as an elevated plus-maze, which consists of two open arms and two closed arms connected to a central platform. Anxiety is gauged as a function of the amount of time a rat spends in the closed versus the open arms of the maze during a 5-minute testing period – the greater an animal's level of anxiety, the less open-arm activity it displays.
Dr. Pandey and his colleagues also found that levels of CREB, a protein involved in a variety of brain functions, were lower in certain brain areas of P rats compared with NP rats. Levels of neuropeptide Y (NPY), a molecule that regulates the function of several neurotransmitters and is known to play a role in anxiety and alcohol-drinking behaviors, also were lower in P rats. One function of CREB is to regulate the production of NPY.
"Compared to NP rats, levels of CREB and NPY were innately lower in the central amygdala and medial amygdala of P rats," explains Dr. Pandey, "brain areas which play a crucial role in anxiety behaviors and which have been shown previously to be involved in rewarding, reinforcing, and motivational aspects of alcohol drinking behaviors. And turning off CREB function in the central amygdala of NP rats makes them look like P rats – more anxious and thus more likely to drink."
Alcohol intake reduced anxiety-like behaviors in the P rats, an effect that was associated with increased CREB function and NPY production in the central and medial amygdala. And by administering compounds that promote CREB function and NPY production in the central amygdala, researchers were able to reduce anxiety -- and alcohol intake -- in P rats. On the other hand, by disrupting CREB function (and the concomitant NPY production) in the central amygdala of NP rats, the researchers were able to provoke anxiety-like behavior and promote alcohol intake in those animals.
Dr. Pandey and his colleagues proposed that decreased CREB-dependent NPY production in the central amygdala might be a pre-existing condition for anxiety and alcohol-drinking behaviors.
"Our findings implicate this pathway in genetic predisposition to high anxiety and alcohol-drinking behaviors of P rats," says Dr. Pandey. "Future studies should explore the relationship of other CREB-related compounds to these phenomena in P rats or other animal models."
The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of the U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at www.niaaa.nih.gov.
Journal
Journal of Clinical Investigation