Alcohol is the most commonly abused addictive substance in the world. Chronic exposure to it causes neuroadaptations in specific areas of the brain, leading to changes in the body that stimulate excessive alcohol consumption. “Alcohol use disorder is a complex psychiatric illness characterized by periods of excessive consumption and periods of abstinence,” say researchers from the Chobanian & Avedisian School of Medicine at Boston University. Currently, alcohol use disorder (AUD) is poorly treated and there are only three treatments available, none of which are very effective. That’s why the researchers conducted a study, the results of which were published in the journal eNeuro.
Alcohol increased PACAP levels in the brains of mice during abstinence
As part of their work, they focused on an area of the brain known as the Bed Nucleus of the Stria Terminalis (BNST), which plays a key role in chronic and pathological alcohol consumption. This area of the brain has particularly high levels of pituitary adenylate cyclase activating polypeptide (PACAP), an important mediator of the stress response.
Carrying out an experiment on mice, the Boston University team found that, during abstinence, the mice had high levels of PACAP in the bed nucleus of the stria terminalis compared to control mice. In other words, they found that this peptide, which is involved in excessive alcohol consumption, acted on the BNST. The authors also found that a similar increase was also observed in the levels of calcitonin gene related peptide (CGRP), another stress neuropeptide closely associated with PACAP. These two peptides have been implicated in stress and pain sensitivity.
PACAP inhibition in the BNST reduced excessive ethanol consumption
Next, the researchers used a virus to block the PACAP-containing neuronal pathways that specifically reach the BNST. By mitigating or inhibiting PACAP in the BNST, the heightened stress response associated with alcohol withdrawal can be reduced. This is crucial because the stress and discomfort of withdrawal are significant factors that drive relapse in individuals with AUD.
“We found that inhibiting PACAP in the BNST significantly reduced excessive ethanol consumption,” explains Valentina Sabino, co-author of the study. The team believes that these results prove that this protein mediates the addictive properties of alcohol and that it can be used as a target “for the development of new pharmacological therapies”.
Miracle, S., Ferragud, A., Seiglie, M. P., Shafique, S., Ozturk, Z., Minnig, M. A., Medeiros, G., Cottone, P., & Sabino, V. (2023). Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice. eNeuro, ENEURO.0424-23.2023. https://doi.org/10.1523/ENEURO.0424-23.2023