Alcohol is the most common addictive substance in the world. Every year in the US excessive alcohol use costs $249 billion and causes about 88,000 deaths, as well as various chronic diseases and social issues. Alcohol use disorder, a highly prevalent, chronic, relapsing disorder, affects more than 14 million people in the US alone, in addition to being severely undertreated, with only three moderately effective pharmacological treatments available.
Chronic alcohol exposure has been shown to cause profound neuroadaptations in specific brain regions, including the recruitment of key stress neurotransmitters, ultimately causing changes in the body that sustain excessive alcohol consumption. The brain region known as the “striate bed nucleus” (BNST) is critically involved in the behavioral response to stress as well as chronic, pathological alcohol use.
Researchers from the Chobanian University & Avedisian School of Medicine in Boston have identified that a peptide called pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in heavy drinking. In addition, they discovered that this peptide acts in the BNST region.
Using an established experimental model for heavy, intermittent alcohol consumption, 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, 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 well established.
The researchers then used a virus in a transgenic model to block PACAP-containing neural pathways that specifically reach the BNST. “We found that inhibiting PACAP in the BNST dramatically reduced heavy ethanol consumption,” explained co-corresponding author Valentina Sabino, PhD, co-director of the School’s Laboratory of Addictive Disorders and professor of pharmacology, physiology and biophysics.
According to the researchers, these results provide evidence that this protein mediates the addictive properties of alcohol.
We have found a key factor, PACAP, that leads to excessive alcohol consumption, which can be targeted for the development of new pharmacological treatments.”
Pietro Cottone, PhD, co-corresponding author, associate professor of pharmacology, physiology and biophysics and co-director of the Addictive Disorders Laboratory
These findings appear online in the journal eNeuro.
Funding for this study was provided by grants number AA026051 (PC), AA025038 (VS), and AA024439 (VS) from the National Institute on Alcohol and Alcoholism (NIAAA), 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).
