Ameliorative Effects of High‐Intensity Interval Training (HIIT) and Methylphenidate Against Tramadol‐Induced Cognitive Impairment: The Role of Hippocampal Oxidative Stress

Background Tramadol (TM) abuse results in significant cognitive dysfunction. This study aimed to investigate the impact of an 8‐week high‐intensity interval training (HIIT) regimen and methylphenidate (MPH) administration (alone and in combination) on cognitive function and hippocampal oxidative stress markers following chronic TM administration. Methods Fifty‐six adult male rats (200–250 g) were divided into eight groups and received one of the following treatments: tramadol (50 mg/kg, intraperitoneally, 5 days/week for the first month and 3 days/week for the second month), methylphenidate (10 mg/kg, intraperitoneally, 3 times/week for 60 days), HIIT (five sessions/week for 8 weeks), or saline (1 mL, intraperitoneally, daily for 60 days). Learning and memory were assessed using the Morris water maze (MWM) and passive avoidance tests. Hippocampal malondialdehyde (MDA), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were measured using TBARS and FRAP methods, respectively. Hippocampal nitric oxide (NO) levels were determined with a commercial assay kit. Results Tramadol induced significant impairments in learning and memory ( p < 0.001). MPH, HIIT, and their combination attenuated these deficits. Tramadol and MPH increased MDA and NO levels ( p < 0.001) and reduced TAC ( p < 0.001). In contrast, HIIT reduced these parameters, even in the presence of MPH. In fact, HIIT reversed the adverse effects of tramadol and MPH by reducing MDA and NO ( p < 0.001) and by increasing GPx ( p < 0.05) and TAC ( p < 0.001). Conclusion Although both MPH and HIIT interventions show promise in mitigating tramadol‐induced cognitive deficits, their mechanisms of action appear to differ significantly. HIIT likely exerts its effects by modulating oxidative stress, whereas MPH seems to disrupt it, suggesting distinct underlying mechanisms. Further studies are required to elucidate these mechanisms in greater detail.