Excessive alcohol consumption is a widespread problem that not only leads to numerous chronic diseases and social issues but also incurs significant economic costs. In the United States alone, excessive alcohol use costs a staggering $249 billion annually and is responsible for approximately 88,000 deaths. Alcohol use disorder, which affects over 14 million people in the U.S., remains severely under-treated, with only three moderately effective pharmacological therapies available.
Chronic exposure to alcohol has been proven to cause significant neuroadaptations in specific areas of the brain, leading to changes in the body that sustain excessive drinking. One such area is the bed nucleus of the stria terminalis (BNST), which plays a critical role in the body’s response to stress as well as chronic alcohol use.
Researchers from Boston University Chobanian & Avedisian School of Medicine have recently identified a peptide called pituitary adenylate cyclase-activating polypeptide (PACAP) as a key mediator in heavy alcohol drinking. They have also discovered that this peptide acts specifically in the BNST.
Using an established experimental model for heavy, intermittent alcohol drinking, the researchers noticed increased levels of the stress neuropeptide PACAP selectively in the BNST during withdrawal compared to the control group. Interestingly, they also observed a similar increase in the levels of another stress neuropeptide closely related to PACAP, known as calcitonin gene-related peptide (CGRP). While the role of both peptides in stress and pain sensitivity has been studied, their involvement in alcohol addiction remains less understood.
To further investigate the role of PACAP in heavy alcohol consumption, the researchers utilized a virus in a transgenic model to block the neural pathways containing PACAP that specifically arrive in the BNST. The results were remarkable, as inhibiting PACAP in the BNST led to a significant reduction in heavy ethanol drinking, according to co-corresponding author Valentina Sabino, Ph.D., co-director of the School’s Laboratory of Addictive Disorders and professor of pharmacology, physiology & biophysics.
The researchers believe that these findings provide compelling evidence that PACAP plays a crucial role in the addictive properties of alcohol. They consider PACAP to be a key player in driving heavy alcohol consumption and a potential target for the development of novel pharmacological therapies for alcohol addiction, as stated by co-corresponding author Pietro Cottone, Ph.D., associate professor of pharmacology, physiology & biophysics and co-director of the Laboratory of Addictive Disorders.
These findings, which have been published in the journal eNeuro, shed light on the intricate biological mechanisms underlying excessive alcohol consumption and provide promising insights for future therapeutic interventions. By understanding the role of PACAP in alcohol addiction, researchers can guide the development of more effective pharmacological treatments to combat this pervasive issue.