Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase

Abstract

We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2′-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake.

Does physical activity protect against drug abuse vulnerability?

“…However, when access to a running wheel is implemented either before or after daily operant conditioning sessions, a decrease in intravenous self-administration also is obtained across different various drugs, including cocaine (Smith et al, 2008b;, methamphetamine (Engelmann et al, 2013;Miller et al, 2012), heroin (Smith and Pitts, 2012) and morphine (Hosseini et al, 2009). Physical activity also decreases the escalation of self-administration (Engelmann et al, 2013;Zlebnik et al, 2012) and reinstatement (Lynch et al, 2010;Sanchez et al, 2013;Thanos et al, 2013;Zlebnik et al, 2010). Especially relevant to human tobacco cessation treatments, physical activity also decreases reinstatement of nicotine seeking following a period of extinction .…”

“…For example, within the hippocampal-prefrontal-amygdala stress axis, repeated exercise training increases bromodeoxyuridine immunoreactivity in hippocampus of rats and mice (Crews et al, 2004;Engelmann et al, 2013;van Praag et al, 1999), indicative of increased neurogenesis. In addition, physical activity enhances proliferation of glial cells in mPFC (Mandyam et al, 2007).…”

Exercise as a Prevention for Substance Use Disorder: a Review of Sex Differences and Neurobiological Mechanisms

“…Results from studies in male and female animals corroborate these findings, and demonstrate that exercise, such as wheel and treadmill running, decrease the acquisition of drug self-administration and levels of drug use (e.g., 8). Results from preclinical studies have also shown that exercise can prevent the development of addiction-like behaviors, such escalation, or the progressive increase in drug use over time (9), indicating that exercise may not only prevent drug use initiation, but may also prevent the development of features of substance use disorder. Exercise has also been suggested as a sex-specific treatment for substance use disorder, and evidence for these effects was reviewed in Part II (10; also see 11).…”

“…Despite these promising results, recent data from both humans and animals suggest that certain exercise conditions may enhance risk of drug use (e.g., 9,12). For example, involvement in certain sports is associated with higher levels of drug and alcohol use, with findings that vary between males and females and between different sports (12–13).…”

“…For example, involvement in certain sports is associated with higher levels of drug and alcohol use, with findings that vary between males and females and between different sports (12–13). While such findings are likely attributable, at least in part, to socio-cultural factors (14–16), findings in animals have also revealed that certain exercise conditions enhance vulnerability to drug use and the development of features of addiction (9) suggesting that biological factors also contribute. The occurrence of protective versus risk-enhancing effects is likely determined by the underlying neurobiology (17), which can depend on a number of factors including the exercise type and schedule of availability, substance used/self-administered, phase of substance use disorder, and sex.…”