The amygdala and alcohol dependence

TSRI scientists find that targeting certain neurons can negate alcohol dependence

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LA JOLLA, Calif.—It’s well known that a drinking addiction reinforces itself; the more a person drinks, the more they need to drink to feel an effect as their body develops tolerance. But drug use also establishes a reward pathway in the brain, which plays a role in dependence. New research in animal models at The Scripps Research Institute (TSRI) targeted that circuit to see if or how it could be affected.
The work in question, “Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala Is Required for Alcohol Dependence,” was published in The Journal of Neuroscience. As noted in the paper, “Abstinence from alcohol is associated with the recruitment of neurons in the central nucleus of the amygdala (CeA) in nondependent rats that binge drink alcohol and in alcohol-dependent rats. However, whether the recruitment of this neuronal ensemble in the CeA is causally related to excessive alcohol drinking or if it represents a consequence of excessive drinking remains unknown. We tested the hypothesis that the recruitment of a neuronal ensemble in the CeA during abstinence is required for excessive alcohol drinking in nondependent rats that binge drink alcohol and in alcohol-dependent rats.”
The TSRI team wanted to determine if it was possible to influence only the neurons that form the circuits in question; those neurons comprise only about 5 percent of the neurons in the brain’s central amygdala. The work was conducted in rat models of alcohol dependence, specifically ones that express a protein to distinguish only the neurons activated by alcohol. Giordano de Guglielmo, a TSRI research associate, was first author of the study that was led by Olivier George, a TSRI assistant professor. These rat models offered new insight into how dependence and reward circuits form in the brain, where it is difficult to identify alcohol-linked neurons without protein labels.
When the rats were injected with a compound that specifically inactivates only alcohol-linked neurons—Daun02, a prodrug—their compulsive drinking completely stopped, which remained the case for as long as they were monitored. When the experiment was repeated two more times, the results were the same: the compulsive alcohol consumption stopped. The authors noted in their abstract that “These results identify a critical neurobiological mechanism that may be required for the transition to alcohol dependence, suggesting that focusing on the neuronal ensemble in the CeA may lead to a better understanding of the etiology of alcohol use disorders and improve medication development.”
“We’ve never seen an effect that strong that has lasted for several weeks,” said George. “I wasn’t sure if I believed it.”
The rats did continue drinking sugar water even after Daun02 administration, which seems to prove that only alcohol-activated neurons were targeted, instead of the brain’s entire reward system.
According to the National Council on Alcoholism and Drug Dependence, Inc., some 17.6 million people—one in 12 adults—suffer from either alcohol abuse or alcohol dependence, and “alcoholism is the third leading lifestyle-related cause of death in the nation.” In alcohol-dependent individuals, beyond the brain’s establishment of the reward pathway, withdrawal symptoms themselves make weaning off of alcohol difficult—symptoms can include shaking, agitation, anxiety and increased blood pressure and heart rate, with the first symptoms appearing as early as eight hours after an individual’s last drink. One of the most promising results of this TSRI study was that the rats seemed to be protected from the detrimental physical effects of withdrawal.
This work also illustrated the difference between casual binge-drinking and dependent drinking in the brain. For the former, when the alcohol-linked neurons were shut off, drinking habits were not greatly affected; instead, the brain switched on a new group of neurons, seemingly implying that the reward path was not cemented yet.
As for what they’ll target next, the team noted in a press release that they will be working to track how alcohol-activated neuronal circuits form over time and look for a way to translate their findings to humans.

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