Relapse to uncontrolled drinking after periods of sobriety is a defining characteristic of alcoholism and is often triggered by stress. A new study in rats reports that a specific receptor for a stress-response transmitter may play an important role in stress-induced relapse. The study, a collaboration between scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH), and at Camerino University, Italy, appears online in the Early Edition of the Proceedings of the National Academy of Sciences on October 2, 2006.

“This finding helps untangle the complex interplay of genetic and environmental factors that influence relapse,” says NIAAA Director T-K Li, M.D. “It also points to potential approaches for treating individuals at risk for relapse.”

Anita C. Hansson, Ph.D., a fellow in NIAAA’s Laboratory of Clinical and Translational Studies, and other NIAAA scientists worked with Camerino University scientists to examine stress-induced relapse in rats that were bred to have a greater-than-normal preference for alcohol.

“These animals provide an excellent model for identifying genes involved in stress-mediated relapse,” says Dr. Hansson. “Not only do they voluntarily consume large amounts of alcohol they also display anxiety and depression-like traits, characteristics that are common among human alcoholics and which indicate a maladaptive response to stress.”

A series of behavioral experiments confirmed that the alcohol-preferring rats were more sensitive to stressful situations. For example, they explored a new environment significantly less than did the normal rats, and also remained immobile longer than normal rats did in the novel environment. Each group of rats then learned that, by pressing a bar, they gained access to as much alcohol as they cared to drink. Under these conditions, the alcohol-preferring rats consume more than twice the amount of regular rats, and do so in order to obtain the intoxicating effects of alcohol. This behavior was extinguished, or unlearned, by a 15-day period during which bar-pressing yielded no alcohol, thus allowing the alcohol-preferring rats to achieve a state of sobriety.

Investigators then assessed whether a stressful stimulus — mild electric foot shock — would induce the rats to again seek alcohol by resuming the bar- pressing behavior. Alcohol-seeking was reinstated in the alcohol-preferring rats by foot shocks of much lower intensity than normal rats required.

“The resumption of alcohol-seeking by alcohol-preferring rats under these conditions is analogous to stress-induced relapse to drinking by human alcoholics,” says NIAAA Clinical Director Markus Heilig, M.D., Ph.D., a senior author of the paper.

To determine if a particular gene or genes might underlie the stress-induced drinking of the alcohol-preferring rats, the researchers compared gene expression patterns in the brains of rats from each group. They focused on several families of known stress-related genes, including those associated with corticotropin-releasing hormone (CRH), which influences behavioral responses to stress through a number of different receptors. They found that alcohol-preferring rats had higher expression levels of Crhr1, a gene encoding the corticotropin-releasing hormone receptor 1 (CRH-R1). Subsequent experiments showed that antalarmin, a compound that blocks CRH-R1, suppressed alcohol drinking and completely blocked stress-induced reinstatement of drinking in alcohol-preferring rats, but had no effect on normal rats. Dr. Heilig notes that NIAAA and other NIH institutes have begun to develop antalarmin for human use.

“Our findings demonstrate that the Crhr1 genotype and its expression interact with environmental stress to reinstate alcohol-seeking behavior in this animal model of excessive drinking,” says Dr. Hansson. She and her colleagues conclude that their data, “provide a functional validation for antagonism at CRH-R1 receptors as a mechanism for novel treatments aimed at relapse prevention in susceptible individuals.”

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting 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.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.