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More than 15 million Americans abuse alcohol, trapped in a downward spiral where they need to ingest more alcohol in order to ease severe withdrawal symptoms. Many admit they simply can’t help themselves. But the latest findings by Scripps Research scientists could be a silver lining for numerous struggling alcoholics. Researchers found that activating a receptor in the brain of alcohol-addicted rats induced them to drink less and eased withdrawal symptoms.

The brain’s seat for alcohol

More than a decade ago, researchers who were combing through the human genome looking for genetic sequences that resemble known receptors came across a G-protein coupled receptor (GPCR) called GPR139. This class of receptors plays a key role in brain signaling, some of which have been previously linked to mental disorders, such as depression, schizophrenia, and drug-induced psychosis.

Subsequent research had shown that GPR139 is primarily found in the habenula, a brain region that mediates some forms of emotive decision-making by influencing the release of dopamine and serotonin. For instance, by inhibiting dopamine-releasing neurons, habenula activation leads to the suppression of motor behavior when an animal fails to obtain a reward or anticipates an aversive outcome. Moreover, the habenula is involved in behavioral responses to pain, stress, anxiety, sleep, and reward.

Olivier George, associate professor at Scripps Research and lead author of the new study, suspected that GPR139 might play a role in addiction, seeing how the habenula is activated during drug and alcohol withdrawal.

“We’ve been very interested in the habenula because this is the area of the brain that produces withdrawal symptoms, which an animal or human then tries to avoid by taking another drink or another dose of a drug,” said George in a statement.

Olivier George, PhD, associate professor at Scripps Research. Credit: Scripps Research.

In an experiment, George and colleagues gave 12 non-alcohol-dependent rats and 17 alcohol-dependent rats an experimental compound called NJ-63533054, which activates GPR139. The drug had no effect on the alcohol intake of the non-alcohol-dependent rats. However, it significantly decreased the amount of alcohol ingested by the rats addicted to alcohol. 

The JNJ-63533054 compound was particularly effective for one-subgroup of rats: those that had the highest alcohol intake and showed compulsive drinking behavior. These rats had such a severe drinking problem that they would continue to ingest alcohol even when it was adulterated with a bitter taste, which should have normally been repulsive for them. This behavior suggests that the targeted receptor is activated when the rats are drinking a lot and going through withdrawal.

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During alcohol withdrawal, the pain threshold in rats (and humans) is generally lower. In order to confirm their findings, the researchers tracked the pain threshold of 17 rats undergoing alcohol withdrawal. When the rodents were treated with JNJ-63533054, they later had a higher threshold for pain. Yet again, the effects were strongest in the rats with the most compulsive drinking behavior.

Finally, in another experiment, the researchers delivered JNJ-63533054 directly to small areas of the brain through thin tubes. Rats ingested less alcohol when the drug was sent to the habenula, but not other brain areas. This confirmed the habenula’s role in alcohol addiction.

The experiments were performed exclusively on male rats, but the researchers suspect that the findings should carry over female rats, too. What’s more, the habenula is involved in broader types of addiction, meaning JNJ-63533054 might ease other types of addiction, besides alcohol.

“The good thing about this type of target is that is almost exclusively expressed in the brain, which limits side effects, and it seems to have no effect on individuals who are not dependent,” says George. “Those are both positive indications of the receptor being druggable.”

The findings appeared in the journal eNeuro.