Researchers at the Ernest Gallo Clinic and Research Center, University of California-San Francisco, report in the June 14 issue of Cell that the brain chemical messenger dopamine and ethanol (beverage alcohol) act through independent mechanisms to synergistically produce a common cellular response that sustains voluntary alcohol consumption. The work may provide an additional target for pharmacologic treatment of alcoholism.

"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 bg 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 bg 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 bg 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 bg dimers. The injection reduced both alcohol consumption and alcohol preference in the animals, lending further support to a significant role of bg dimers in voluntary drinking.

"Our experiments suggest that synergy of dopamine D2 and adenosine A2 receptors creates hypersensitivity to ethanol and that bg 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 press@cell.com 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.