Heavy alcohol drinking and withdrawal in mice is linked to pituitary adenylate cyclase activating polypeptide (PACAP), according to work by researchers from Boston University Chobanian & Avedisian School of Medicine. PACAP is found in the bed nucleus of the stria terminalis (BNST). Further, the team found that inhibiting PACAP in the BNST significantly reduces the mice’s alcohol consumption, offering a potential target for novel treatments in people.
Their work appeared in eNeuro recently. The lead author is Lauren Lepeak of the Boston University School of Medicine.
“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,” they write.
The world’s most common addiction, alcohol use disorder, leads to $249 billion in annual costs and 88,000 deaths in the U.S., but is under-treated. A highly prevalent, chronic, relapsing disorder, alcohol use disorder affects more than 14 million people in the U.S. alone. There are only three modestly effective pharmacological therapies available, and they are severely underused.
The genetics of drug and alcohol abuse have proven to be difficult to unravel. Research suggests genetic differences in individual physiology, drug- or alcohol-induced changes in epigenetic gene regulation and expression, and developmental and environmental factors all contribute to the development and persistence of chronic substance abuse.
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 BNST is critically involved in the behavioral response to stress as well as in chronic, pathological alcohol use.
These authors write, “Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed.”
Using an experimental model for heavy, intermittent alcohol drinking, the Boston University Medical School researchers observed that during withdrawal this model showed increased levels of the stress neuropeptide PACAP selectively in the BNST, compared to the control model.
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 arrives 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,” said co-corresponding author Pietro Cottone, PhD, associate professor of pharmacology, physiology & biophysics and co-director of the Laboratory of Addictive Disorders.