Exercise during early, but not late abstinence, attenuates subsequent relapse vulnerability in a rat model

Abstract

Exercise has shown promise as a nonpharmacological intervention for addiction, with evidence suggesting a potential utility for relapse prevention. In humans, exercise as an intervention is typically introduced well after the initiation of abstinence, yet neurobiological data from preclinical studies suggest that it may be more effective if initiated during early abstinence. Here, using rat models, we determined whether the beneficial effects of exercise on relapse vulnerability depends on when exercise is first initiated, during early versus late abstinence. Once rats (n=47) acquired cocaine self-administration, they were given 24-h access to cocaine (1.5 mg/kg per infusion) under a discrete trial procedure (four infusions per hour) for 10 days. The rats then began a 14-day abstinence period in which they had access (2 h per day) to a locked wheel throughout abstinence (sedentary) or an unlocked wheel during early (days 1–7), late (days 8–14) or throughout (days 1–14) abstinence (n=10–14 per group). Cocaine seeking, as assessed under an extinction/cued-induced reinstatement procedure, was examined on day 15 of abstinence. Exercise beginning during early abstinence robustly attenuated subsequent cocaine seeking, and this effect persisted even when exercise ended on the seventh day of abstinence. In contrast, exercise during late abstinence was not effective and these animals displayed high levels of cocaine seeking similar to those observed in sedentary animals. These results indicate that the timing of exercise availability differentially impacts cocaine seeking with results suggesting that exercise during early, but not late, abstinence may provide long-term protection against cocaine relapse.

Exercise as a Sex-Specific Treatment for Substance Use Disorder

“…Although few controlled trials have been conducted on exercise as a relapse intervention for other drugs of abuse, several recent pilot studies conducted in individuals, mostly men, undergoing treatment for substance use disorder demonstrate its feasibility and potential efficacy (26–33). Similar findings have been reported in male and female laboratory animals with results showing that exercise during abstinence, such as voluntary running in a wheel or forced running on a treadmill, reduces drug withdrawal signs (34–40), including craving (41–43), and prevents the development of incubation of drug-craving (44–52), an animal model of relapse defined by a progressive increase in drug-craving over abstinence (53). Exercise has also been suggested as a sex-specific prevention for substance use disorder, and evidence for these effects was reviewed in Part I (54; also see 55).…”

“…This anti-relapse effect of exercise has been observed in males and females, adolescent and adult-onset models, for multiple drugs of abuse (cocaine, nicotine, methamphetamine), and for cue-, context-, and drug-induced craving, but not stress-induced craving (44–52). Although levels of running do not consistently predict effects on the incubation of craving (64–65), effects become more pronounced with increasing exercise access such that high access (≥6-hr/day) blocks the incubation effect (46–47).…”

“…The timing of exercise availability during abstinence also appears to be critical for inducing protective effects (44). For example, results in male rats showed that wheel running beginning during early abstinence (days 1–7) robustly decreased subsequent cocaine-craving (day 15), whereas exercise beginning later during abstinence (days 8–14), was not effective, and in some cases, increased craving (44).…”

“…For example, results in male rats showed that wheel running beginning during early abstinence (days 1–7) robustly decreased subsequent cocaine-craving (day 15), whereas exercise beginning later during abstinence (days 8–14), was not effective, and in some cases, increased craving (44). These findings are striking given that the time from the last exercise session to reinstatement testing was much longer in the early exercise group, and suggests that if exercise is properly timed during abstinence, it can provide enduring protection against relapse.…”

“…While lack of power and compliance issues undoubtedly contribute to the variability (24– 29,56–59), results from animal studies also demonstrate that certain exercise conditions may not be effective, and some may even increase relapse vulnerability (44,49). The ability of exercise to reduce or enhance withdrawal symptoms/craving and relapse vulnerability is likely determined by the underlying neurobiology which can vary between males and females, exercise conditions, drugs of abuse, and early versus later abstinence time-points (2).…”