"Today's report fast-forwards efforts to understand the precise brain mechanisms involved in alcohol-seeking behavior," said National Institute on Alcohol Abuse and Alcoholism Acting Director Raynard S. Kington, M.D., Ph.D. "Extending this work in animal and human studies may advance the development of medications to impede alcohol-seeking behavior and prevent relapse in dependent drinkers."
Considerable previous research indicates that dopamine release within the brain's natural reward center, either in anticipation of drinking or during exposure to alcohol, contributes to incentive processes and alcohol consumption. In ßg Dimers Mediate Synergy of Dopamine D2 and Adenosine A2 Receptor-Stimulated PKA Signaling and Regulate Ethanol Consumption, Ivan Diamond, M.D., Ph.D., and his colleagues demonstrate a biological mechanism for this response.
The researchers showed in rat cell cultures that dopamine binding to one of its receptors (D2 subtype) generates signaling proteins known as ßg dimers that, through a series of events, cause the activation of protein kinase A (PKA), another protein involved in intracellular communication, gene expression, and animal behavioral responses to alcohol. Although acting through a different receptor (adenosine type 2, or A2), ethanol generates the same signaling protein and subsequent activation of PKA. Further, dopamine and ethanol applied together to the cells at concentrations that individually would not activate PKA signaling produced a synergistic response between the A2 and D2 receptors that increased ßg dimer formation and, in turn, generated PKA signaling.
To explore whether the cellular effects produced a behavioral response, the researchers examined alcohol-drinking behavior in rats injected with a scavenger molecule designed to reduce the level of dimers. The injection reduced both alcohol consumption and alcohol preference in the animals, lending further support to a significant role of dimers in voluntary drinking.
"Our experiments suggest that synergy of dopamine D2 and adenosine A2 receptors creates hypersensitivity to ethanol and that ßg dimers are required to sustain voluntary drinking," said Dr. Diamond.
NIAAA and the State of California, with additional funding from the Irwin Green Research Fund in Neurosciences and the Leo and Julia Forchheimer Center for Molecular Genetics at the Weizmann Institute of Science in San Francisco, supported the research.
To obtain a copy of the article, please contact firstname.lastname@example.org or telephone Kamela Hutzley at 617/397-2826 at Cell. For an interview with Dr. Diamond, please contact Wallace Ravven, UCSF News Services, 415/476-2557 and for an interview with Dr. Kington, contact the NIAAA Press Office. For additional alcohol research information, visit www.niaaa.nih.gov.
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 U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.