Sex-specific Concordance of Striatal Transcriptional Signatures of Opioid Addiction in Human and Rodent Brains. Sex-specific Concordance of Striatal Transcriptional Signatures of Opioid Addiction in Human and Rodent Brains

Background: Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current treatments for OUD are unsuccessful in lead to lasting abstinence in most users. This underscores the lasting effects of chronic opioid use and emphasizes the need to understand the molecular mechanisms of drug seeking and taking, but also how those alterations persist through acute and protracted withdrawal. Methods: Here, we used RNA sequencing in post-mortem human tissue from males (n=10) and females (n=10) with OUD and age and sex-matched control subjects. We compared molecular alterations associated with human OUD in the nucleus accumbens (NAc) to mouse and rat models of non-volitional (n=3-6 per group per sex) and volitional (n=5-6 per group per sex) exposure to opioids across distinct stages of opioid use and withdrawal (acute and prolonged). Results: We found that the molecular signature in the NAc of females with OUD mirrored effects seen in the NAc of female rodents in a non-volitional paradigm at all stages of exposure. Conversely, males with OUD showed a similar expression profile to rodents with volitional exposure, but only during the acute withdrawal phase. Shared co-expression networks were involved in post-transcriptional modification of RNA and epigenetic modification of chromatin state. Conclusions: Our results provide fundamental insight into the conserved molecular pathways altered by opioids across species, with evidence suggesting that alterations in females with OUD may be driven by drug exposure, while alterations in males with OUD may be driven by volitional intake. Overall design: RNA-sequencing was conducted on prefrontal cortex and nucleus accumbens of Heterogeneous Stock rats and C57BL/6J mice. Both male and female rats and mice were used. Heterogeneous Stock rats underwent oxycodone self-administration, then sacrificed at different times following opioid self-administration. Mice were given either saline solution or morphine solution for oral drinking, then sacrified at different times following opioid drinking. Tissue was collected and gene expression was examined in rats and mice across different times of opioid administration and withdrawal.

背景：阿片类使用障碍（Opioid use disorder, OUD）已成为一场严重且持续的公共卫生紧急事件。当前针对OUD的治疗手段无法使大多数使用者实现长期戒断。这既凸显了慢性阿片类药物使用的持久影响，也强调了我们需要深入理解药物觅取与服用的分子机制，以及这些分子改变如何在急性和迁延性戒断阶段持续存在。

方法：本研究针对罹患OUD的男性（n=10）与女性（n=10）受试者，以及年龄、性别匹配的对照受试者的死后人体组织，开展RNA测序（RNA sequencing）分析。我们将伏隔核（nucleus accumbens, NAc）中与人类OUD相关的分子改变，与阿片类药物使用及戒断不同阶段（急性及迁延阶段）下，非自愿性暴露（每组每性别3-6例）与自愿性暴露（每组每性别5-6例）的小鼠、大鼠模型进行了对比。

结果：我们发现，罹患OUD的女性受试者的伏隔核分子特征，与所有暴露阶段下采用非自愿性给药范式的雌性啮齿类动物伏隔核中的改变相一致。与之相反，罹患OUD的男性受试者的基因表达谱仅在急性戒断阶段，与采用自愿性给药范式的啮齿类动物相似。共有的共表达网络涉及RNA的转录后修饰以及染色质状态的表观遗传修饰。

结论：本研究结果为跨物种间阿片类药物诱导的保守分子通路改变提供了基础性见解，同时有证据表明，女性OUD患者的分子改变可能由药物暴露直接驱动，而男性OUD患者的分子改变则可能由自愿性药物摄入所驱动。

整体实验设计：我们对远交系大鼠（Heterogeneous Stock rats）与C57BL/6J小鼠的前额叶皮层及伏隔核开展RNA测序。实验同时使用了雄性与雌性大鼠及小鼠。远交系大鼠接受羟考酮自身给药训练，随后在阿片类药物自身给药后的不同时间点处死。小鼠经口给予生理盐水或吗啡溶液，随后在阿片类药物饮用后的不同时间点处死。收集组织并检测不同阿片类药物给药及戒断阶段下，大小鼠的基因表达水平。