Repeated stress enhanced cocaine self-administration equally in male and female rats, but blocking CB1 receptors reduced cocaine intake through different mechanisms in each sex.
Addiction researchers, neuroscientists studying sex differences, and clinicians interested in cannabinoid system involvement in substance use disorders.
What the researchers found
Footshock stress increased cocaine self-administration in both sexes. In males, CB1 antagonism only reduced cocaine intake in rats with combined stress-and-cocaine history. In females, rimonabant reduced cocaine intake even without stress history, with stressed females sensitive to both doses tested.
Why it matters
Stress is a major driver of drug relapse, and sex differences in addiction mechanisms are increasingly recognized. The cannabinoid system mediates stress-cocaine interactions differently in males and females.
The numbers in context
Cocaine dose: 0.5 mg/kg/infusion. Rimonabant doses: 1 and 3 mg/kg. Females showed stress-specific front-loading behavior. Both rimonabant doses effective in stressed females.
How the study worked
Male and female Sprague-Dawley rats self-administered cocaine during sessions with or without footshock stress. CB1 receptor antagonist rimonabant administered systemically at two doses (1 and 3 mg/kg).
What this study cannot tell us
Rat models may not fully translate to human cocaine use disorder. Only one stress paradigm tested. Systemic rimonabant affects the whole body.
How to read the evidence
Well-designed animal study with appropriate controls and both sexes, but limited to one stress paradigm.
When this study was published
2025 publication.
The bigger picture
This adds to growing evidence that addiction biology differs meaningfully between sexes. The endocannabinoid system appears more broadly involved in cocaine-taking in females, regardless of stress.
Questions still open
- Would CB1 receptor modulators be more effective for treating cocaine addiction in women than men?
- What brain circuits mediate the sex-specific CB1R effects?
Common questions
Why does the cannabinoid system matter for cocaine addiction?
What does this mean for treating cocaine addiction differently in men and women?
Read the original research
Repeated footshock stress enhances cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1.
Physiology & behavior, 293, 114840
Citation
Gaulden, Andrew D; Tepe, Erin A; Sia, Eleni; Rollins, Sierra S; McReynolds, Jayme R. (2025). Repeated footshock stress enhances cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1.. Physiology & behavior, 293, 114840. https://doi.org/10.1016/j.physbeh.2025.114840
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