Exercise intensity and testosterone modulate cognitive recovery and BDNF levels during morphine abstinence in castrated male rats

Chronic opioid exposure and subsequent abstinence are associated with persistent cognitive impairment and disrupted neuroplasticity, which may be further aggravated by opioid-induced hypogonadism. Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal plasticity in memory-related brain regions; however, the combined effects of exercise intensity and testosterone replacement during morphine abstinence remain poorly understood. This study investigated whether mild- and moderate-intensity treadmill exercise, alone or in combination with testosterone replacement, could ameliorate cognitive deficits and restore BDNF levels in morphine-abstinent castrated male rats. Rats underwent sham surgery or bilateral castration, followed by a 30-day recovery period, induction of morphine dependence (10 mg/kg, twice daily for 10 days), and a 28-day intervention consisting of sedentary conditions or treadmill exercise with or without testosterone treatment. Spatial learning and memory were evaluated using the Morris water maze, and avoidance memory was assessed using the shuttle box task. BDNF levels in the hippocampus, prefrontal cortex, and serum were quantified by ELISA. Morphine abstinence and castration impaired spatial learning, spatial memory, and avoidance memory and significantly reduced hippocampal and prefrontal cortex BDNF levels. Both mild- and moderate-intensity exercise improved cognitive performance and increased hippocampal and prefrontal cortex BDNF levels, with moderate-intensity exercise generally producing greater benefits. Testosterone replacement partially ameliorated the adverse effects of castration and improved selected behavioral and neurochemical outcomes, although its effects varied across experimental conditions. These findings suggest that appropriately prescribed exercise is an effective non-pharmacological strategy for promoting cognitive recovery and restoring neurotrophic signaling during morphine abstinence, while testosterone replacement may provide additional benefit under hypogonadal conditions. Chronic morphine and castration impair spatial and avoidance memory. Exercise improves cognition and restores brain BDNF during morphine abstinence. Moderate exercise produces greater cognitive benefits than mild exercise. Testosterone partially restores cognition and BDNF after castration. Exercise and testosterone may aid cognitive recovery during opioid abstinence.