Peptide PACAP’s Key Role in Alcohol Addiction

Summary: Alcohol, the world’s most common addictive substance, leads to $249 billion in annual costs and 88,000 deaths in the U.S. Alcohol use disorder affects millions but is under-treated.

Researchers discovered a key player in alcohol addiction: pituitary adenylate cyclase activating polypeptide (PACAP). This peptide, found in the “bed nucleus of the stria terminalis” (BNST), is linked to heavy alcohol drinking and withdrawal.

Inhibiting PACAP in the BNST significantly reduces alcohol consumption, offering a potential target for novel treatments.

Key Facts:

  1. Alcohol use disorder is a prevalent and under-treated condition with significant social and economic costs.
  2. Chronic alcohol exposure leads to neuroadaptations in the brain, including the BNST.
  3. Researchers identified PACAP as a key factor in heavy alcohol drinking and potential therapy target.

Source: Boston University

Alcohol is the most common addictive substance in the world. Every year in the U.S. excessive alcohol use costs $249 billion and causes approximately 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 U.S. alone, in addition to being severely under-treated, with only three modestly effective pharmacological therapies available.

This shows a man and empty drinking glasses.
The researchers then used a virus in a transgenic model to block the neural pathways containing PACAP that specifically arrive to the BNST. Credit: Neuroscience News

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.

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.

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, PhD, 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, PhD, associate professor of pharmacology, physiology & biophysics  and co-director of the Laboratory of Addictive Disorders.
 

These findings appear online in the journal eNeuro.

Funding: 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).

About this alcohol use disorder and neuroscience research news

Author: Gina DiGravio
Source: Boston University
Contact: Gina DiGravio – Boston University
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice” by Valentina Sabino et al. eNeuro


Abstract

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice

Alcohol use disorder (AUD) is a complex psychiatric disease characterized by periods of heavy drinking and periods of withdrawal. Chronic exposure to ethanol causes profound neuroadaptations in the extended amygdala, which cause allostatic changes promoting excessive drinking.

The bed nucleus of the stria terminalis (BNST), a brain region involved in both excessive drinking and anxiety-like behavior, shows particularly high levels of pituitary adenylate cyclase activating polypeptide (PACAP), a key mediator of the stress response.

Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed; whether the PACAP system of the BNST is also recruited in other models of alcohol addiction and whether it is of local or non-local origin is currently unknown.

Here, we show that PACAP immunoreactivity is increased selectively in the BNST of C57Bl/6J mice exposed to a chronic, intermittent access to ethanol.

While PAC1R expressing cells were unchanged by chronic alcohol, the levels of a peptide closely related to PACAP, the calcitonin gene related neuropeptide (CGRP), were found to also be increased in the BNST.

Finally, using a retrograde chemogenetic approach in PACAP-ires-Cre mice, we found that the inhibition of PACAP neuronal afferents to the BNST reduced heavy ethanol drinking.

Our data suggest that the PACAP system of the BNST is recruited by chronic, voluntary alcohol drinking in mice and that non-locally originating PACAP projections to the BNST regulate heavy alcohol intake, indicating that this system may represent a promising target for novel AUD therapies.

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