Exercise Pills for Drug Addiction: Forced Moderate Endurance Exercise Inhibits Methamphetamine-Induced Hyperactivity through the Striatal Glutamatergic Signaling Pathway in Male Sprague Dawley Rats

Abstract

Physical exercise reduces the extent, duration, and frequency of drug use in drug addicts during the drug initiation phase, as well as during prolonged addiction, withdrawal, and recurrence. However, information about exercise-induced neurobiological changes is limited. This study aimed to investigate the effects of forced moderate endurance exercise training on methamphetamine (METH)-induced behavior and the associated neurobiological changes. Male Sprague Dawley rats were subjected to the administration of METH (1 mg/kg/day, i.p.) and/or forced moderate endurance exercise (treadmill running, 21 m/min, 60 min/day) for 2 weeks. Over the two weeks, endurance exercise training significantly reduced METH-induced hyperactivity. METH and/or exercise treatment increased striatal dopamine (DA) levels, decreased p(Thr308)-Akt expression, and increased p(Tyr216)-GSK-3β expression. However, the phosphorylation levels of Ser9-GSK-3β were significantly increased in the exercise group. METH administration significantly increased the expression of NMDAr1, CaMKK2, MAPKs, and PP1 in the striatum, and exercise treatment significantly decreased the expression of these molecules. Therefore, it is apparent that endurance exercise inhibited the METH-induced hyperactivity due to the decrease in GSK-3β activation by the regulation of the striatal glutamate signaling pathway.

Messenger RNA expression profiles and bioinformatics analysis of mouse hippocampi during exercise alleviates methamphetamine dependence via mRNA profile change in hippocampi

“…Similarly, it has been confirmed in animal studies that the self-administered METH dosage is significantly reduced in mice that voluntarily run on wheels ( 32 - 34 ). Since most drug users lead sedentary lives, studies have reported that rats were subjected to moderate endurance-forced exercise rather than voluntary exercise to mimic the exercise stress conditions found clinically ( 6 , 35 ). In this study, moderate-intensity forced running was used to intervene in the acute withdrawal period of METH-addicted mice.…”

“…The CPP test was conducted every day before the exercise intervention until there was no significant difference between the CPP test and the pretest score for 2 consecutive days, indicating that the CPP had disappeared. The exercise group received treadmill training at a speed of 10 meters/minute, an inclination of 0°, and an acceleration of 8 meters/minute for 45 minutes/day, lasting 7 days in total ( 6 ). All treadmill sessions were scheduled from 9:00 am to 11:30 am.…”

“…Therefore, new treatments are urgently needed for drug addicts. Recent studies have found that scientific and appropriate exercise interventions based on the above treatment methods can improve the psychological state of drug addicts, strengthen their physical fitness, and promote their physical and mental rehabilitation (5)(6)(7). Long-term regular exercise has been shown to exert a significant ameliorative effect on METH withdrawal symptoms and reduces METH relapse (4).…”

Potential Effects of Nrf2 in Exercise Intervention of Neurotoxicity Caused by Methamphetamine Oxidative Stress

“…Therefore, exercise may mitigate METH-induced neurotoxicity by preventing BBB destruction in the hippocampus and associated microenvironmental changes [ 96 ]. In SD rats, forced moderate endurance exercise also inhibits METH-induced hyperactivity through the glutamate signaling pathway [ 97 ]. It is not difficult to conclude that the key link between METH-induced neurological damage and the benefits brought by exercise may be the regulation of oxidative stress mechanisms in the above [ 98 ].…”

“…Both preclinical and clinical studies reported that Nrf2 had a protective effect on METH-induced oxidative stress and inflammation, even neuronal degeneration [ 41 ]. The Nrf2-mediated antioxidant pathway can prevent neurodegenerative effects and functional defects caused by oxidative stress in METH [ 60 , 97 ].…”