Background:Forced exercise can act as non-pharmacologic neuroprotective agent. In current study, we tried the involved molecular mechanisms of protective effects of forced exercise against methamphetamine induced neurodegeneration.Materials and Methods:Forty adult male rats were divided to Group 1 and 2 which received normal saline and methamphetamine (10 mg/kg) respectively for 30 days. Groups 3, 4 and 5 were treated with methamphetamine for first 15 days and then were treated by forced exercise, bupropion (20 mg/kg/day) or combination of them for the following 15 days. Between 26th and 30th days, Morris Water Maze (MWM) was used to evaluate the cognition. On day 31, hippocampus was isolated from each rat and oxidative, antioxidant and inflammatory factors also the level of total and phosphorylated forms of cAMP response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) proteins were also evaluated.Results:Chronic abuse of methamphetamine could decreases cognition and increase malondialdehyde (MDA), Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), while caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities all these changes was significant (P < 0.001) in compared to control group while treatment with bupropion, forced exercise and bupropion in combination with forced exercise could prevent all these malicious effects of methamphetamine (P < 0.001). Bupropion, forced exercise and bupropion in combination with forced exercise could activate CREB (both forms) and activates BDNF proteins’ expression with P < 0.001 in methamphetamine treated rats.Conclusions:P-CREB/BDNF signaling pathways might have critical role in forced exercise protective effects against methamphetamine induced neurodegeneration.