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Scientists Identify New Key Mediator in Heavy Alcohol Drinking

Researchers at Boston University have identified a peptide, PACAP, in the brain as a key contributor to heavy alcohol drinking. By inhibiting PACAP in the brain’s BNST area, their study significantly reduced alcohol consumption, suggesting new avenues for treating alcohol addiction.

Alcohol ranks as the world’s most widespread addictive substance. In the United States, the annual cost of excessive alcohol consumption amounts to $249 billion, and it leads to roughly 88,000 fatalities each year, along with numerous chronic health conditions and societal problems. Over 14 million individuals in the U.S. suffer from alcohol use disorder, a commonly occurring, chronic, and recurrent condition. Despite its prevalence, this disorder is often inadequately treated, with only three moderately effective drug treatments currently available.

Chronic exposure to alcohol has been shown to produce profound neuroadaptations in specific brain regions, including the recruitment of key stress neurotransmitters, ultimately causing changes in the body that sustain excessive drinking. The area of the brain known as the “bed nucleus of the stria terminalis” (BNST) is critically involved in the behavioral response to stress as well as in chronic, pathological alcohol use.

Breakthrough Research on Alcohol Addiction

Researchers from Boston University Chobanian & Avedisian School of Medicine have identified that a peptide called pituitary adenylate cyclase-activating polypeptide (PACAP), is involved in heavy alcohol drinking. In addition, they have discovered that this peptide acts in the BNST area.

Using an established experimental model for heavy, intermittent alcohol drinking, the researchers observed that during withdrawal this model showed increased levels of the stress neuropeptide PACAP selectively in the BNST, compared to the control model.

Interestingly, a similar increase was also observed in the levels of another stress neuropeptide closely related to PACAP, the calcitonin gene-related peptide, or CGRP. Both peptides have been implicated in stress as well as pain sensitivity, but their role in alcohol addiction is less established.

Findings on PACAP’s Role in Alcohol Addiction

The researchers then used a virusA virus is a tiny infectious agent that is not considered a living organism. It consists of genetic material, either DNA or RNA, that is surrounded by a protein coat called a capsid. Some viruses also have an outer envelope made up of lipids that surrounds the capsid. Viruses can infect a wide range of organisms, including humans, animals, plants, and even bacteria. They rely on host cells to replicate and multiply, hijacking the cell's machinery to make copies of themselves. This process can cause damage to the host cell and lead to various diseases, ranging from mild to severe. Common viral infections include the flu, colds, HIV, and COVID-19. Vaccines and antiviral medications can help prevent and treat viral infections.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>virus in a transgenic model to block the neural pathways containing PACAP that specifically arrive to the BNST. “We found that inhibiting PACAP to the BNST dramatically reduced heavy ethanol drinking,” explained co-corresponding author Valentina Sabino, Ph.D., co-director of the School’s Laboratory of Addictive Disorders as well as professor of pharmacology, physiology & biophysics.

According to the researchers, these results provide evidence that this protein mediates the addictive properties of alcohol. “We found a key player, PACAP, driving heavy alcohol drinking, which can be targeted for the development of novel pharmacological therapies,” added co-corresponding author Pietro Cottone, Ph.D., associate professor of pharmacology, physiology & biophysics and co-director of the Laboratory of Addictive Disorders.

Reference: “Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice” by Lauren Lepeak, Sophia Miracle, Antonio Ferragud, Mariel P. Seiglie, Samih Shafique, Zeynep Ozturk, Margaret A. Minnig, Gianna Medeiros, Pietro Cottone and Valentina Sabino, 1 December 2023, eNeuro.
DOI: 10.1523/ENEURO.0424-23.2023

Funding for this study was to grants number AA026051 (PC), AA025038 (VS), and AA024439 (VS) from the National Institute on Alcohol and Alcoholism (NIAAA), the Boston University Undergraduate Research Opportunities Program (UROP), the Boston University Micro and Nano Imaging Facility and the Office of the Director of the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>National Institutes of Health (S10OD024993).

Source: SciTechDaily