REVIEW article
Front. Behav. Neurosci.
Sec. Motivation and Reward
This article is part of the Research TopicThe moderating role of sex and gender on brain function and behaviorView all articles
Sex differences in stress-modulated cocaine vulnerability: female rodents are more sensitive to the effects of stress exposure at different developmental stages
Provisionally accepted
María Ángeles Martínez-Caballero1
Claudia Calpe López2
MARIA Pilar GARCIA PARDO3
Maria Carmen Arenas1
Carmen Manzanedo1
Maria Asuncion Aguilar1*- 1University of Valencia, Valencia, Spain
- 2Universitat Heidelberg, Heidelberg, Germany
- 3Universidad de Zaragoza, Zaragoza, Spain
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Introduction: Stressful life events can trigger the initiation of cocaine use, facilitate transition to a cocaine use disorder (CUD) and precipitate relapse. Evidence suggests that women progress more rapidly to a CUD than men. Thus, the influence of stressful life events on CUD development may differ by sex, contributing to the enhanced vulnerability seen among females. In this work, we provide a comprehensive (non-systematic) review of clinical and preclinical studies comparing the effects of cocaine and its modulation by stress in both sexes. Methods: We performed a search of the Pubmed database (1986-2025) in which we combined the keywords "cocaine" and "stress" with "sex differences" or "female rat" or "female mice" or "women". We then read the abstracts of the search results to select potentially relevant studies, which we read in full to determine if they fulfilled our criteria and to extract the relevant information. Results: Sex is overlooked as a biological variable in preclinical and clinical research. The results of clinical studies indicate the existence of sex differences in the response to stress among individuals with CUD. Preclinical studies strongly suggest that female rodents are more vulnerable to developing addiction-like features than male rodents, particularly in the self-administration paradigm. Furthermore, exposure to stress appears to amplify the effects of cocaine, particularly in females. Discussion: There is growing evidence that women and female rodents are more vulnerable to the behavioral and neurochemical changes that characterize cocaine addiction. The influence of sex should be considered in research and in the selection of strategies for preventing and treating CUD, including those targeting stress reduction.
Keywords: Cocaine use disorder, sex differences, Animal Models, Addiction, stress, females
Received: 20 Aug 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Martínez-Caballero, Calpe López, GARCIA PARDO, Arenas, Manzanedo and Aguilar. 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: Maria Asuncion Aguilar, asuncion.aguilar@uv.es
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.