Department of Pharmacology, Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Mol Psychiatry. 2023 Nov;28(11):4777-4792. doi: 10.1038/s41380-023-02241-6. Epub 2023 Sep 6.
Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)-key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24-h cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes associated with vesicle-mediated transport and membrane trafficking in the NAc and platelet-derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.
阿片类药物成瘾和复发易感性与严重和持续的睡眠及昼夜节律紊乱有关。了解昼夜节律和阿片类药物使用障碍（OUD）的神经生物学基础，可能有助于开发治疗阿片类药物成瘾的新方法。先前的工作表明，与 OUD 相关的人类大脑中的分子节律紊乱，突出了背外侧前额叶皮层（DLPFC）和伏隔核（NAc）中的突触改变——这两个大脑区域与认知和奖励有关，并且与 OUD 的病理生理学密切相关。为了进一步深入了解 OUD 中的突触改变，我们使用基于质谱的蛋白质组学方法，对未受影响和 OUD 受试者的 DLPFC 和 NAc 的大块组织和突触体制剂中的蛋白质表达变化进行了深度分析。我们在未受影响和 OUD 受试者的 DLPFC 匀浆中鉴定出 55 个差异表达（DE）蛋白，在 NAc 匀浆中鉴定出 44 个 DE 蛋白。在突触体中，我们在 OUD 受试者的 DLPFC 和 NAc 中分别鉴定出 161 个和 56 个 DE 蛋白。通过比较匀浆和突触体蛋白表达，我们鉴定出在 OUD 受试者的 DLPFC 和 NAc 中特异性富集且明显改变的突触蛋白。在整个脑区中，OUD 受试者的突触蛋白改变主要发生在谷氨酸、GABA 和昼夜节律信号中。通过使用死亡时间（TOD）分析，将每个受试者的 TOD 用作 24 小时周期内的时间点，我们能够在与 NAc 中囊泡介导的转运和膜运输以及 DLPFC 中血小板衍生生长因子受体β信号相关的突触蛋白质组中映射与 OUD 相关的昼夜节律变化。总的来说，我们的研究结果进一步支持了人类大脑中突触信号的分子节律紊乱是阿片类药物成瘾的关键因素。
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