Effects of voluntary exercise and sex on multiply-triggered heroin reinstatement in male and female rats

J. R. Smethells, A. Greer, B. Dougen, M. E. Carroll

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background: The rise in heroin addiction has heightened the need for novel and effective treatments. Physical exercise has been shown as an effective treatment for stimulant abuse in clinical and pre-clinical research. However, this treatment has not yet been tested on opioid addiction. This study examined the effects of physical activity (wheel running) on heroin-seeking in rats within a reinstatement paradigm (i.e., heroin relapse model). Methods: Female and male rats were trained to self-administer intravenous heroin (0.015 mg/kg). Once trained, rats were placed into extinction (i.e., heroin abstinence) for 21 days with continuous access to a locked or unlocked running wheel. After extinction, rats were tested for drug- (heroin, caffeine, and yohimbine) and cue-primed reinstatement of heroin-seeking. Results: Females completed more wheel revolutions than males across all study phases. Access to an unlocked running wheel reduced extinction and reinstatement of heroin-seeking, with greater reductions in females than males across several reinstatement conditions. In the locked wheel group, female rats showed greater reinstatement of heroin-seeking than males across several priming conditions. Conclusions: Wheel running reduced heroin-seeking in male and female rats, with females showing a more robust effect during reinstatement. The locked wheel group allowed an examination of sex differences in heroin reinstatement, which revealed that females showed greater vulnerability to heroin reinstatement than males, but with no other sex differences observed in maintenance or extinction. Overall, the results indicate that voluntary physical exercise may be an effective treatment for heroin dependence in humans.

Original languageEnglish (US)
Pages (from-to)453-463
Number of pages11
Issue number2
StatePublished - Feb 1 2020

Bibliographical note

Funding Information:
This study was supported by NIH/NIDA P50 DA033942 (MEC) and a NIDA training grant T32 DA007097 (JRS; PI: Dr. Thomas Molitor).

Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.


  • Exercise
  • Heroin reinstatement
  • Rats
  • Running wheel
  • Sex differences


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