Department of Neuroscience, Perelman School of Medicine, Mahoney Institute for Neurosciences, University of Pennsylvania, 415 Curie Blvd, Philadelphia, PA, 19104, USA.
Sci Rep. 2023 May 25;13(1):8460. doi: 10.1038/s41598-023-35673-9.
The effectiveness of current treatments for opioid use disorder (OUD) varies by sex. Our understanding of the neurobiological mechanisms mediating negative states during withdrawal is lacking, particularly with regard to sex differences. Based on preclinical research in male subjects, opioid withdrawal is accompanied by increased gamma-aminobutyric acid (GABA) release probability at synapses onto dopamine neurons in the ventral tegmental area (VTA). It is unclear, however, if the physiological consequences of morphine that were originally elucidated in male rodents extend to females. The effects of morphine on the induction of future synaptic plasticity are also unknown. Here, we show that inhibitory synaptic long-term potentiation (LTP) is occluded in the VTA in male mice after repeated morphine injections and 1 day of withdrawal, while morphine-treated female mice maintain the ability to evoke LTP and have basal GABA activity similar to controls. Our observation of this physiological difference between male and female mice connects previous reports of sex differences in areas upstream and downstream of the GABA-dopamine synapse in the VTA during opioid withdrawal. The sex differences highlight the mechanistic distinctions between males and females that can be targeted when designing and implementing treatments for OUD.
当前治疗阿片类药物使用障碍（OUD）的方法在性别上存在差异。我们对介导戒断期间负面状态的神经生物学机制了解不足，特别是关于性别差异方面。基于男性动物的临床前研究，阿片类药物戒断伴随着腹侧被盖区（VTA）多巴胺神经元上突触 GABA 释放概率增加。然而，吗啡最初在雄性啮齿动物中阐明的生理后果是否扩展到女性，目前还不清楚。吗啡对未来突触可塑性诱导的影响也尚不清楚。在这里，我们表明，在反复吗啡注射和 1 天戒断后，雄性小鼠的 VTA 中抑制性突触长时程增强（LTP）被阻断，而吗啡处理的雌性小鼠仍然能够诱发 LTP，并且 GABA 活性与对照组相似。我们观察到雄性和雌性小鼠之间的这种生理差异，将先前关于 VTA 中 GABA-多巴胺突触上下游区域在阿片类药物戒断期间性别差异的报告联系起来。这些性别差异突出了在设计和实施 OUD 治疗时可以针对男性和女性的机制区别。
