According to a new study activating a receptor found in brain cells may help treat alcohol addiction and ease some withdrawal symptoms. The researchers studied the effects of activating the receptor in alcohol-addicted rats and reported the results in the journal eNeuro.
"The big takeaway here is that we have a new molecular target linked to alcohol addiction," says the senior author. "This is something that will trigger a lot more research and hopefully eventually lead to the discovery of new medicines not only for alcohol addiction but drug addiction in general."
An estimated 15 million adults in the United States have alcohol use disorder--compulsive alcohol drinking and a loss of control over alcohol intake. Today, there are three medications approved by the Food and Drug Administration to treat alcohol addiction, but each has weaknesses and limitations.
In 2005, researchers sifting through the human genome for new receptors--looking for genetic sequences that resembled known receptors--uncovered a G-protein coupled receptor (GPCR) dubbed GPR139. GPCRs play a large role in brain signaling, and some have been linked to mental disorders. Since discovering GPR139, scientists have shown that the receptor is primarily found in an area of the brain called the habenula. Since the habenula is activated during drug and alcohol withdrawal, researchers wondered whether GPR139 might play a role in addiction.
In the new work, the group took advantage of an experimental compound, known as JNJ-63533054, that activates GPR139. They gave the compound orally to 12 non-alcohol-dependent male rats and 17 alcohol-dependent rats. The compound had no effect on the alcohol intake of animals that weren't already dependent on alcohol or on the water intake of alcohol-addicted animals. But it did significantly decrease the alcohol intake of alcohol-addicted rats.
When the researchers looked more closely at the rats, they discovered that JNJ-63533054 was particularly effective at decreasing drinking in one subgroup of animals: those that had the highest alcohol intake and showed compulsive drinking behavior. These rats were so addicted to alcohol, that they would normally continue to drink even when their alcohol was adulterated with a bitter taste.
"What this tells us is that this receptor is activated when you're drinking a lot and going through withdrawal," says the senior author.
The pain threshold of rats--or humans--undergoing alcohol withdrawal is generally lower than normal, so to make a further connection between GPR139 and withdrawal, the scientists tracked the pain threshold of 17 rats going through alcohol withdrawal. When the rats were treated with JNJ-63533054, they found, the animals had a higher threshold for pain. Similar to the first experiment, the effect was strongest in rats that had the highest levels of compulsive drinking behavior.
This suggests that, once again, GPR139 is activated during withdrawal only in severe cases of alcohol addiction, senior author says, and the drug helps mediate the physical pain associated with withdrawal in these cases.
Finally, the team used thin tubes to deliver JNJ-63533054 to small areas of the brain. The drug decreased alcohol intake when it was infused into the habenula, they found, but not other brain areas, confirming the importance of the brain region in addiction and withdrawal.
While the research was only performed in male rats, and only alcohol addiction was studied, the senior author suspects the results will hold true both for females and for other drug addiction, since the habenula has been shown to be critical in drug withdrawal more broadly.
"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 the senior author. "Those are both positive indications of the receptor being druggable."
New target for alcohol addiction
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