The principal finding of this study is that long-term voluntary exercise decreases sensitivity to the positive-reinforcing effects of cocaine in female rats. Breakpoints maintained by cocaine on the PR schedule of reinforcement were significantly lower in exercising rats than sedentary rats, and this effect was apparent at both low and high doses of cocaine. In the high-dose condition, exercising rats reached a final ratio value that was less than one third the ratio value reached by sedentary rats (70 vs. 240). When these values are considered in terms of total number of responses per session, exercising rats emitted approximately 600 fewer responses per session than sedentary rats (270 vs. 1000). Importantly, these reductions in responding translated into a lower number of cocaine infusions (11 vs. 16) and a lower amount of cocaine intake (3.0 mg vs. 4.5 mg) during each self-administration session. Collectively, these data suggest the exercise may have “protective effects” on cocaine-seeking behavior, possibly by reducing the motivation to engage in behaviors that lead to cocaine self-administration.
Supporting the possibility that exercise was protective in the present investigation, there was a significant negative correlation between exercise output prior to catheter implantation and cocaine-maintained breakpoints after catheter implantation. In other words, those rats that ran the most prior to catheter implantation self-administered significantly less cocaine when it was later made available on the PR schedule. These data suggest that exercise may produce an output-dependent effect on those neuronal substrates that mediate the positive-reinforcing effects of cocaine. If this is correct, then greater levels of physical activity may result in greater degrees of protection from cocaine’s positive-reinforcing effects. Such a conclusion must be viewed with caution, however, as a significant correlation was not observed in the low dose condition, nor were significant correlations observed when exercise output after catheter implantation was used in the regression analysis.
As reported previously (Smith and Yancey, 2003
; Smith and Lyle, 2006
), exercise output gradually increased over the first 3 weeks of wheel exposure before leveling out until behavioral testing commenced. Exercise output decreased in all rats by approximately 50% with the acquisition of self-administration and then remained consistent until the end of behavioral testing. It is unlikely that these reductions were due to catheter implantation per se, as exercise output typically returns to baseline levels within 48 to 72 hours in the absence of drug administration (personal observations). It is also unlikely that these reductions can be attributed to the fact that rats were prevented from running during the self-administration sessions. Microanalysis studies of female rats reveal that over 95% of wheel running occurs during the dark phase of the light/dark cycle and less than 1% occurs during the first 3 hours of the light phase of the cycle (Eikelboom and Mills, 1988
), the period of time in which self-administration sessions were conducted. Such reductions in wheel running reported in the present study may be due to depletion of central dopamine stores induced by repeated exposure to high doses of cocaine. Consistent with this possibility, a number of studies report that dopamine depletion induced by 6-hydroxydopamine lesions (Derevenco et al., 1986
; Isobe and Nishino 2001
), 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine lesions (Leng et al., 2004
; Nakajima and Minematsu, 2006
), and repeated amphetamine administration (Serwatkiewicz et al., 2000
) markedly reduces exercise output in laboratory rats and mice.
In order to preserve the ecological validity of the study, no attempt was made to control or manipulate the estrous cycle. Previous studies report that hormonal fluctuations due to the estrous cycle can influence day-to-day variability in both running wheel activity (Steiner et al., 1982
; Kent et al., 1991
) and cocaine self-administration (Roberts et al., 1989
; Feltenstein and See, 2007
); however, it is unlikely that such day-to-day fluctuations could have accounted for the present results. For instance, on the PR schedule, all rats remained at a given dose until a stable breakpoint was reached. Based on our operational definition, a stable breakpoint could only be obtained after a minimum of 3 days, and we were able to obtain stable breakpoints in all rats at both doses of cocaine. Furthermore, all correlational analyses were conducted using exercise output data that were averaged over several weeks of data collection, thus masking any day-to-day fluctuations in running wheel activity. Although forced-exercise procedures serve as behavioral stressors and disrupt normal estrous cycling (Chatterton et al., 1990
; Caston et al., 1995
), voluntary exercise procedures do not produce estrous cycle disruptions or hormonal abnormalities (Dixon et al., 2003
; Mathes and Kanarek, 2001
). Although estrous cycle was not monitored in the present study, gonadal hormones were likely within the normal range of variability for both sedentary and exercising subjects.
Although it was not the aim of this study to determine the mechanism by which exercise alters the reinforcing efficacy of cocaine, a few possibilities deserve attention. One potential explanation for the decreased responding in exercising rats involves behavioral fatigue induced by wheel running. Although this is perhaps the most parsimonious explanation for the observed differences in cocaine-maintained responding, several pieces of data argue against this possibility. For instance, behavioral fatigue would be expected to affect all measures of operant responding. Although differences were observed in cocaine-maintained responding, no significant differences were observed in responding maintained by saline or in the number of inactive lever presses. Also, if wheel running immediately prior to the experimental session led to behavioral fatigue during the session, then exercise output during the period of time in which behavioral testing took place should be inversely related to responding. As noted above, this was not the case, and only exercise output prior to catheter implantation was predictive of cocaine self-administration.
Another possible explanation for our findings involves potential pharmacokinetic differences in the absorption, distribution, and metabolism of cocaine between sedentary and exercising subjects. Previous studies report that exercising rats have lower body weights, less adipose tissue, and smaller livers than sedentary rats (Pitts and Bull, 1977
), any of which could alter the bioavailability of cocaine. Studies that have specifically compared plasma concentrations of cocaine in sedentary and exercising subjects have typically reported that exercise increases its bioavailability. For instance, Han et al. (1996)
reported that plasma concentrations of cocaine were 69% greater in a group of forced exercise rats than in a group of rested control rats. Such increases in plasma concentrations would be expected to increase, not decrease, the reinforcing efficacy of cocaine in exercising subjects, thus making pharmacokinetic differences an unlikely explanation for our findings.
A third potential explanation for our findings involves exercise serving as an alternative, non-drug reinforcer to decrease cocaine self-administration. Although exercise can serve as an alternative, non-drug reinforcer when both are concurrently available (Kanarek et al., 1995
, Cosgrove et al., 2002
), a running wheel was never available during the self-administration sessions in the present study, and test sessions were scheduled at a time of day in which wheel running was a low-probability behavior. A previous study examining the circadian control of running reports that wheel activity is low during the first 3 hours of the light phase of the light/dark cycle (i.e., when all test sessions took place), and is virtually absent between the third and ninth hour of the light phase (Eikelboom and Mills, 1988
). Consequently, the effects of exercise on cocaine-maintained breakpoints cannot be attributed to its ability to function as an alternative reinforcer either during or immediately after the self-administration sessions.
One additional explanation for the differences reported in the present study involves pharmacodynamic changes in those neuronal pathways that contribute to the positive reinforcing effects of cocaine. Several pieces of evidence suggest that acute bouts of exercise produce effects that are neurochemically similar to those produced by cocaine and other psychomotor stimulants. For instance, like cocaine, exercise increases central dopamine concentrations (Heyes et al., 1988
; Hattori et al., 1994
; Meeusen et al., 1997
; Petzinger et al., 2007
), and these increases are positively correlated with exercise output (Freed and Yamamoto, 1985
). Importantly, chronic, long-term exercise leads to sustained increases in dopamine concentrations (Bauer et al., 1989
) and compensatory changes in dopamine binding proteins (Fisher et al., 2004
). Studies focusing specifically on the dopamine D2
receptor have typically reported an increase in D2
receptor density following chronic exercise (Gilliam et al., 1984
; MacRae et al., 1987
). The D2
receptor plays an important modulatory role in cocaine’s reinforcing effects (Nader et al., 1999
; Caine et al., 2000
; Khroyan et al., 2000
), and there is an increasing body of evidence that the reinforcing effects of psychomotor stimulants are inversely related to D2
receptor density. For instance, in humans, the psychomotor stimulant methylphenidate is rated as less pleasurable and more aversive in people with high D2
receptor density than in people with low D2
receptor density (Volkow et al., 1999
). In studies with non-human primates, social housing increases D2
receptor density in dominate males while simultaneously decreasing their propensity to self-administer cocaine (Morgan et al., 2002
). It is possible that exercise produces its protective effects on cocaine self-administration via similar mechanisms; specifically, by producing functional alterations in those dopamine binding proteins that are critical for psychomotor stimulant reward.
Although exercise is not a standard component of most drug abuse prevention and treatment programs, those that do employ a physical fitness component have generally reported positive effects. For instance, a 12-week training program targeting adolescents and focusing on learning values and life skills through exercise reported a significant decrease in several risk factors associated with substance abuse and a concomitant reduction in the percentage of individuals who use cigarettes, smokeless tobacco, and alcohol (Collingwood et al., 2000
). Similarly, a drug intervention program targeting at-risk adolescents and including an 8-week structured exercise class reported a significant decrease in anxiety, depression, and substance use in those participants exhibiting an improvement in physical fitness (Collingwood et al., 1991
). Studies examining the efficacy of physical fitness programs in inpatient treatment facilities have also reported that exercise decreases depression and anxiety risk factors that are associated with relapse (Frankel and Murphy, 1974
; Palmer et al., 1988
). In a residential correctional facility for federal drug offenders, a wellness program that emphasized physical fitness produced improvements in several areas related to psychological well-being, including self-esteem, health awareness, healthy lifestyle adoption, and relapse prevention skills (Peterson and Johnstone, 1995
). Finally, in one of the few studies that examined relapse to substance use after the termination of active treatment, a thrice weekly exercise program significantly increased abstinence rates in recovering alcoholics from 38% to 69% after 3 months (Sinyor et al., 1982
). Such findings, coupled with the present data, suggest that aerobic exercise is an effective intervention for substance abuse and warrants an expanded role in prevention and treatment programs. Importantly, this particular intervention is inexpensive, widely available, easy to execute, and feasible for use in diverse patient populations.