Scientists identify brain mechanism that boosts response to alcohol

Cell molecule could make good target for drug against alcoholism

Neuroscientists at UCSF’s Ernest Gallo Clinic and Research Center (EGCRC) have discovered that a molecule in neurons boosts the brain’s response to alcohol, triggering in minutes chemical changes that maintain an urge to drink alcohol.

Blocking the molecule’s action might prevent excessive drinking, they conclude.

For years researchers have known that alcohol and all other addicting substances activate a brain region known as the nucleus accumbens, principally through the action of the neurotransmitter dopamine.

The study demonstrates how dopamine release in the brain may contribute to alcohol craving and drinking behavior.

The research shows that neurons in the nucleus accumbens may become hypersensitive to alcohol because a signaling molecule links two chemical pathways: one involving dopamine, and the other involving the neuromodulator adenosine.

This combined effect may be required to maintain the urge to drink alcohol, the scientists found.

Alcohol unleashes a "synergy" between the two chemical pathways via the signaling molecule, the researchers discovered, so this molecule may make a promising target for drugs to treat alcoholic cravings and excessive drinking.

The research is reported in the June 14 issue of the journal CELL. The paper describes new discoveries in rat neuron cell cultures that were confirmed in studies of alcohol consumption in rats.

The unexpected agent linking the two processes is known as a Beta-gamma dimer, a signaling molecule in all cells.

Researchers already knew that alcohol triggers a series of chemical steps in neurons through the cell’s adenosine receptor, leading to changes in gene activity. What they discovered is that the Beta-gamma dimer released normally through the neuron’s dopamine receptor, amplifies this adenosine pathway chemical cascade. This boosts the brain’s response to alcohol.

"Synergy is a most remarkable finding," said Ivan Diamond, MD, PhD, UCSF professor of neurology, director of the EGCRC and senior author on the CELL paper “It enables a substance taken into the body – alcohol -- to team up with the normal, ongoing dopamine process to cause an exaggerated response to alcohol. We believe synergy causes hypersensitivity to alcohol in those neurons which have both dopamine and adenosine receptors, as in the nucleus accumbens.

Most neurons in the brain do not have both receptors on the same cell and should not be as responsive to alcohol.

"The other remarkable finding is that Beta-gamma dimers are required for synergy and for voluntary alcohol consumption.

This appears to be the first behavioral response regulated by Beta-gamma dimers and provides a novel target for new medications to prevent or reduce excessive drinking."

"Today’s report fast-forwards efforts to understand the precise brain mechanisms involved in alcohol-seeking behavior," said Raynard S., Kington, MD, PhD, acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

"Extending this work in animal and human studies may fast-forward the development of medications to impede alcohol-seeking behavior and prevent relapse in dependent drinkers."

The NIAAA and the State of California were the primary funders of the research.

All addictive drugs are known to activate neurons in the nucleus accumbens, principally through release of dopamine, and the region is central to the development of cravings and behaviors that are the hallmarks of alcoholism and other addictions, researchers say.

Conventional wisdom has been that adenosine and dopamine receptors usually counterbalance each other.

But the new research shows that in the presence of alcohol, the two pathways actually produce a combined, or synergistic effect.

The research team engineered a hybrid neuron cell culture to express both the dopamine and adenosine receptors, to model normal nucleus accumbens neurons.

When they activated the dopamine receptor, they discovered that this led to activation of a key protein involved in both cell communication and gene expression, known as protein kinase A, or PKA. Once activated, PKA prompts gene activity associated with responses to alcohol.

They demonstrated the synergistic effect by showing that when dopamine and alcohol at low concentrations were introduced to the neurons together, they would activate PKA and gene expression, whereas when introduced separately no activation occurred.

By blocking Beta-gamma dimer activity, the scientists also showed that this molecule is necessary for dopamine and alcohol to work together.

The key role of Beta-gamma dimers was confirmed in studies with rats trained to drink alcohol voluntarily.

When the animals were accustomed to consuming the human equivalent of about two drinks every two hours, the researchers introduced a chemical into the nucleus accumbens that inhibited Beta-gamma dimer activity.

Alcohol consumption promptly dropped, although water consumption was unaffected.

The experiments suggest that Beta-gamma dimers in the nucleus accumbens are required to sustain voluntary drinking, the authors state.

"It is possible that drugs that target Beta-gamma and/or synergy of adenosine and dopamine receptors might prevent, attenuate, or reverse excessive drinking. Studies are underway to test this possibility," they conclude.

Lead author on the paper is Lina Yao, MD, PhD., senior scientist, Ernest Gallo Clinic and Research Center (EGCRC), neurology, UCSF. Co-authors are Maria Pia Arolfo, PhD., postdoctoral fellow; Zhan Jiang, PhD., staff research associate; and Peidong Fan, PhD, specialist, all at EGCRC; Douglas P. Dohrman, PhD., assistant professor, anatomy and neurobiology, Texas A&M University.

Also, Sara Fuchs, PhD., professor, of immunology, Weizmann Institute of Science in Rehovot, Israel; Patricia Janak, PhD., assistant professor of neurology, EGCRC, UCSF; and Adrienne S. Gordon, PhD., professor of neurology and cellular and molecular pharmacology, EGCRC, UCSF.

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