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

Abstract

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. Here, we examined sex differences in the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking. Male and female rats self-administered cocaine (1.5mg/kg/infusion) under extended access conditions (24h/day, 4 discrete trials/h) for 10days. Rats were then given voluntary access to either an unlocked or locked running wheel for 1, 2, 6, or 24h/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. 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 24h/day), but not limited (1 and 2h/day) access to a wheel surmounted the heightened vulnerability observed in females during estrus. Taken together, our findings suggest that the effectiveness of wheel running is dose-, sex-, and estrous cycle-dependent.