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 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.
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 Health (S10OD024993).