Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: impact of sex and estrous cycle in rats

Psychopharmacology (Berl). 2014 Jul;231(13):2661-70. doi: 10.1007/s00213-014-3437-1. Epub 2014 Jan 25.


Rationale: Exercise has shown promise as an intervention for drug addiction; however, little is known regarding the exercise conditions that most effectively reduce relapse vulnerability and whether these conditions differ by sex.

Objective: Here, we examined sex differences in the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking.

Methods: Male and female rats self-administered cocaine (1.5 mg/kg/infusion) under extended access conditions (24 h/day, 4 discrete trials/h) for 10 days. Rats were then given voluntary access to either an unlocked or locked running wheel for 1, 2, 6, or 24 h/day during the 14-day abstinence period. Separate groups of rats were housed in polycarbonate cages during abstinence to control for physical activity that the wheel may provide. Subsequent cocaine-seeking was assessed under a within-session extinction/cue-induced reinstatement procedure. Estrous cycle was monitored in females to determine whether the effectiveness of wheel running varied by estrous cycle phase.

Results: Although females ran more than males, males were more sensitive to the effects of running and showed a dose-dependent decrease in cocaine-seeking with longer access resulting in greater suppression. The dose-effect relationship was less straightforward in females and access to both a locked and unlocked wheel decreased cocaine-seeking with effects dependent on estrous cycle phase. Notably, extended (6 and 24 h/day), but not limited (1 and 2 h/day) access to a wheel surmounted the heightened vulnerability observed in females during estrus.

Conclusion: Taken together, our findings suggest that the effectiveness of wheel running is dose-, sex-, and estrous cycle-dependent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Cocaine / administration & dosage*
  • Cues
  • Drug-Seeking Behavior*
  • Estrous Cycle / physiology
  • Female
  • Male
  • Motor Activity / physiology*
  • Physical Conditioning, Animal / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Running / physiology
  • Self Administration
  • Sex Factors
  • Time Factors


  • Cocaine