Moderate-intensity continuous training modulates the expression of autophagy-related genes in the frontal cortex and improves behavioral responses in rats during methamphetamine withdrawal

Aerobic exercise has been extensively documented as a beneficial intervention for maintaining and enhancing central nervous system function. This study investigated the effects of moderate-intensity continuous training (MICT) during methamphetamine (METH) withdrawal on open-field behaviors and the expression of autophagy-related genes in the frontal cortex of rats. This experimental study included male rats and evaluated the expression of C/EBPβ, DDIT4, TSC-2, mTOR, LC3-II, Nrg-1, and EphB1 genes using real-time PCR, along with behavioral responses assessed by the open field test (OFT). Rats received METH (5 mg/kg/day) for 21 consecutive days, followed by an 9-week withdrawal period with or without MICT. Gene expression and behavioral outcomes were assessed at the end of the respective experimental periods. Statistical analyses were performed separately according to the experimental phases: saline versus METH for the initial phase and METH versus METH-CON for the later phase; the effect of MICT was subsequently evaluated by comparing METH-CON and METH-MICT. Compared with the saline group, METH exposure significantly reduced total distance traveled, velocity, and rearing, while increasing grooming behavior. METH exposure also significantly increased the expression of C/EBPβ, DDIT4, TSC-2, and LC3-II, and significantly decreased the expression of mTOR, Nrg-1, and EphB1 in the frontal cortex. During the withdrawal period, compared with the METH-CON group, MICT significantly increased total distance traveled and rearing and decreased grooming behavior. At the molecular level, MICT significantly decreased LC3-II expression and increased the expression of mTOR, Nrg-1, and EphB1. METH exposure impaired locomotor and exploratory behaviors, increased grooming behavior, and dysregulated autophagy-related signaling in the frontal cortex. MICT during withdrawal attenuated these alterations by improving behavioral outcomes, reducing LC3-II expression, and increasing mTOR, Nrg-1, and EphB1 expression, suggesting a potential role for MICT in promoting recovery from METH-induced neurobehavioral and molecular impairments. Not applicable.