Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy.

成瘾是一个严重的公共卫生问题，目前的药物治疗无法阻止吸毒复吸。研究重点关注体育锻炼作为一种有前途的辅助治疗。我们的研究小组最近表明，多巴胺能系统中与预防安非他明复发相关的有益神经适应涉及体育锻炼诱导的内源性阿片系统激活（EXE-OS 激活）。在这种背景下，人们探索了其他机制来了解运动对毒瘾的益处。先前暴露于安非他明（AMPH，4.0 mg/kg）8天的雄性大鼠进行为期5周的体育锻炼。每次体育锻炼前 5 分钟给予纳洛酮 (0.3 mg/kg) 阻断 EXE-OS 激活。运动方案结束后，将大鼠重新暴露于 AMPH 中 3 天，然后依次实施安乐死并解剖 VTA 和 NAc。在 VTA 中，我们的研究结果显示 proBDNF、BDNF 和 GDNF 的免疫含量增加，AMPH 诱导的 TrkB 水平降低；因此，EXE-OS 激活增加了所有这些标记物，而纳洛酮给药则阻止了这种运动诱发的效应。在 NAc 中，相同的分子标记也因 AMPH 增加而因 EXE-OS 激活而减少。在这项研究中，我们提出 EXE-OS 激活的有益影响与随之而来的中边缘脑区域神经营养素和多巴胺能系统水平的神经适应之间存在密切关系，从而防止观察到的 AMPH 复发行为。我们的结果带来了有关成瘾神经生物学理解的更多知识，并表明 EXE-OS 激活可能是药物成瘾治疗的潜在辅助工具。