Immune proteins may be targets for future treatment of alcohol use disorders

Anxiety that occurs during withdrawal from excessive alcohol use and contributes to recurrence can be partially caused by the release of immune proteins in the brain, according to a new study by Scripps Research scientists.

The discovery was reported online on June 6, 2022. molecule PsychiatryReveals the molecular details of the brain’s response to alcohol withdrawal, suggesting that the immune protein colony-stimulating factor 1 (CSF1) may be a potential future treatment target for alcohol withdrawal disorders (AUD). doing.

Alcohol withdrawal activates the brain’s stress system, which contributes to recurrence. This study links this stress response to the neuroimmune mediator CSF1 and opens up new opportunities for therapeutic intervention... “

Marisa Roberto, PhD, Study Senior Author and Professor and Schimmel Family Chair, Department of Molecular Medicine, Scripps Research

The lead author of this study, which has undergone many experiments, is Dr. Reesha R. Patel, a former postdoctoral fellow at the Roberto Institute.

Alcohol is the most used and abused recreational drug to date. According to the 2019 National Survey on Substance Use and Health, 9 million men and more than 5 million women in the United States suffer from alcohol abuse disorders (AUDs). This is defined as the uncontrollable use of alcohol, even though it has a negative impact on alcohol use. User health, social life and / or employment. Drug therapy, talk therapy, and support group-based therapies are available, but recurrence is common, primarily due to a limited understanding of the underlying brain circuit dysfunction of AUD.

Scientists know that alcohol withdrawal symptoms that promote recurrence include increased anxiety that is at least partially caused by the release of stress molecules such as corticotropic pin-releasing factor (CRF) in the brain. CRF stimulates receptors in neurons of the prefrontal cortex and limbic system. This is a series of more primitive brain structures that process emotions.

If scientists can fully identify and characterize these CRF-sensitive neuronal populations, they will have a better understanding of how anxiety develops during withdrawal and effective treatments to prevent it. There is a possibility that it can be devised.

To that end, in a new study, Roberto and her team identified a population of neurons in the medial prefrontal cortex (mPFC) of mice that are sensitive to CRF to express a CRF receptor called CRF1. Scientists have shown that these neurons are involved in mood and behavioral changes between alcohol exposure and withdrawal symptoms.

The team’s first experiments showed that removing these CRF-sensitive neurons reduced anxiety in mice. This suggests that neurons usually mediate behaviors such as anxiety.

Later, researchers found that these CRF-sensitive mPFC neurons were less likely to excite-; they were less likely to signal other neurons when stimulated-; experience alcohol withdrawal. In alcohol-dependent mice. In contrast, nearby mPFC neurons lacking CRF receptors are more prone to excitement.

“These CRF-sensitive mPFC neurons appear to constitute a unique population of neurons that undergo severe neurological adaptations from chronic alcohol exposure,” said Paulavi Gandhi, a postdoctoral fellow at Roberto Labs, co-author of the study. The doctor says.

Interestingly, researchers have found that alcohol withdrawal induces a significant increase in CSF1 gene expression in these neurons, even though it reduces excitability in CRF-sensitive neurons. CSF1 is the most well-known immune protein in the role of stimulating stem cells to mature into large white blood cells called macrophages.

In the brain, CSF1 is thought to play a similar role in maintaining immune cells in the brain called microglia. In addition, previous studies in mice have shown that under chronic stress conditions, CSF1 production is elevated in mPFC, driving microglia to break connections between neurons, which causes signs of anxiety and depression. Suggests.

Looking more closely at the role of CSF1 in alcohol withdrawal, Roberto et al. Artificially increased CSF1 production in mouse CRF-sensitive mPFC neurons, with many of the same neuronal and behavioral changes seen in animals with alcohol withdrawal. Observed to show. Levels of mPFC can be a major factor in the signs and symptoms of alcohol withdrawal.

“Therefore, targeting CSF1 could be a good strategy for treating AUD and is currently eager to test it in preclinical models,” Patel said. increase.

“Ethanol withdrawal-induced adaptation in frontal corticotropin-releasing factor receptor 1-expressing neurons regulates ethanol anxiety and conditioned reward effects,” Reesha Patel, Sarah Wolfe, Vittoria Borgonetti, Pauravi Gandhi, Larry Rodriguez, Angela Snyder. , Co-authored by Shannon D. ‘Ambrosio, Michal Bajo, Alain Domissy, Steven Head, Candice Contet, R. Dayne Mayfield, Amanda Roberts, Marisa Roberto.