内啡肽调制 5-HT 释放介导阿片类戒断期间的社交缺陷。
Modulation of 5-HT release by dynorphin mediates social deficits during opioid withdrawal.
机构信息
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
出版信息
Neuron. 2022 Dec 21;110(24):4125-4143.e6. doi: 10.1016/j.neuron.2022.09.024. Epub 2022 Oct 5.
Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid withdrawal in mice require activation of kappa opioid receptors (KORs) in the nucleus accumbens (NAc) medial shell. Blockade of release from dynorphin (Pdyn)-expressing dorsal raphe neurons (DR), but not from NAc neurons, prevents these deficits in prosocial behaviors. Conversely, optogenetic activation of DR neurons reproduced NAc KOR-dependent decreases in sociability. Deletion of KORs from serotonin (5-HT) neurons, but not from NAc neurons or dopamine (DA) neurons, prevented sociability deficits during withdrawal. Finally, measurements with the genetically encoded GRAB sensor revealed that during withdrawal KORs block the NAc 5-HT release that normally occurs during social interactions. These results define a neuromodulatory mechanism that is engaged during protracted opioid withdrawal to induce maladaptive deficits in prosocial behaviors, which in humans contribute to relapse.
社交隔离是阿片类药物戒断期间导致当前阿片类药物成瘾危机的主要因素。我们发现，在小鼠长期阿片类药物戒断期间，社交能力缺陷需要在伏隔核（NAc）内侧壳中激活κ阿片受体（KOR）。阻断强啡肽（Pdyn）表达的中缝背核（DR）神经元释放，而不是 NAc 神经元释放，可防止这些亲社会行为缺陷。相反，光遗传学激活 DR 神经元可再现 NAc KOR 依赖性社交能力下降。5-羟色胺（5-HT）神经元而非 NAc 神经元或多巴胺（DA）神经元中的 KOR 缺失可防止戒断期间的社交能力缺陷。最后，使用基因编码的 GRAB 传感器进行的测量表明，在戒断期间，KOR 阻断了 NAc 中通常在社交互动中发生的 5-HT 释放。这些结果定义了一种神经调节机制，该机制在长期阿片类药物戒断期间被激活，以诱导亲社会行为的适应性缺陷，而在人类中，这些缺陷会导致复发。
Zotero 插件