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REVIEW article

Front. Neurosci.
Sec. Translational Neuroscience
Volume 19 - 2025 | doi: 10.3389/fnins.2025.1545810
This article is part of the Research Topic Neurobiological Basis of Substance Use Disorders: New Findings and Perspectives View all articles

Pituitary Adenylate Cyclase-Activating Polypeptide Plays a Role in Neuropsychiatric Disorders and Drug-Abuse: Sex-Specific Perspective

Provisionally accepted
Catherine Elizabeth Van Doorn Catherine Elizabeth Van Doorn 1,2Mikala M Zelows Mikala M Zelows 1,2Anel Ariana Jaramillo Anel Ariana Jaramillo 1,2*
  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, United States
  • 2 University of Kentucky, Lexington, Kentucky, United States

The final, formatted version of the article will be published soon.

    The neuropeptide pPituitary aAdenylate cCyclase-aActivating pPeptide (PACAP) plays a pivotal role in processing stress, fear, and anxiety. Genetic and molecular studies investigating PACAP demonstrate sex dimorphic characteristics, with females exhibiting increased reactivity of PACAP signaling in neuropsychiatric disorders. Studies expand the role of PACAP to substance use disorders (SUD) by demonstrating modulation of PACAP can lead to neurobiological changes induced by nicotine, ethanol, stimulants, and opioids. Given females with SUD exhibit distinct drug-use, relapse, and withdrawal sensitivity relative to males, we hypothesize the PACAP system contributes to these sex-specific differences. Therefore, we review the role of PACAP in SUD by characterizing the role of PACAP at the molecular, brain regional, and behavioral level as it pertains to the cycle of SUD. We present literature in relation to neuropsychiatric disorders which demonstrate the intricate role of PACAP within neuronal signaling and pathways modulating addiction. Altogether we hypothesize females are more susceptible to PACAP-related changes in the intoxication and withdrawal components of the addiction cycle. Altogether understanding sex dimorphisms within the PACAP system provides an opportunity for future studies to develop tailored interventions addressing SUD.

    Keywords: neuropsychiatric disorders, PACAP, drug abuse and addiction, sex differences, Cycle

    Received: 15 Dec 2024; Accepted: 15 Jan 2025.

    Copyright: © 2025 Van Doorn, Zelows and Jaramillo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Anel Ariana Jaramillo, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.