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Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition
Neuropsychopharmacology ( IF 6.6 ) Pub Date : 2021-09-20 , DOI: 10.1038/s41386-021-01168-2
Antony D Abraham 1, 2 , Sanne M Casello 2 , Selena S Schattauer 1, 2 , Brenden A Wong 3 , Grace O Mizuno 4 , Karan Mahe 4 , Lin Tian 4 , Benjamin B Land 1, 2 , Charles Chavkin 1, 2
Affiliation  

Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In C57BL/6 male mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant-delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre- and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdynCre neurons using Channelrhodopsin-2 disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence.



中文翻译:

前额叶皮层内源性强啡肽阿片类药物的释放会扰乱认知

在反复使用阿片类药物后,一些依赖个体会出现持续的认知缺陷,导致吸毒行为复发,而这种反应的一个组成部分可能是由新皮质中的内源性强啡肽/kappa 阿片系统介导的。在 C57BL/6 雄性小鼠中,我们发现急性吗啡戒断会引起内侧前额叶皮层 (PFC) 中的强啡肽释放,并通过激活局部 kappa 阿片受体 (KOR) 破坏认知功能。使用磷酸化 KOR 抗体的免疫组织化学分析证实,戒断诱导和光学诱发的强啡肽释放都激活了 PFC 中的 KOR。使用基于惰性 KOR (kLight1.2a) 的基因编码传感器,我们揭示了 PFC 中内源性强啡肽释放的体内动力学。PFC 中 KOR 的局部激活在操作性延迟交替行为任务中产生记忆处理的多阶段中断,表现为操作性会话早期和晚期响应数量和准确性的降低。在 PFC 中使用选择性 KOR 拮抗剂降二氢托啡肽 (norBNI) 进行局部预处理可在治疗的早期和晚期阻止系统性 KOR 激活的破坏性影响。PFC KORs 的病毒切除阻断了早期而非晚期的破坏,表明突触前和突触后 KORs 在解剖学上可分离。吗啡依赖小鼠的纳洛酮沉淀戒断或光刺激 这表现为在操作会话的早期和晚期阶段响应数量和准确性的减少。在 PFC 中使用选择性 KOR 拮抗剂降二氢托啡肽 (norBNI) 进行局部预处理可在治疗的早期和晚期阻止系统性 KOR 激活的破坏性影响。PFC KORs 的病毒切除阻断了早期而非晚期的破坏,表明突触前和突触后 KORs 在解剖学上可分离。吗啡依赖小鼠的纳洛酮沉淀戒断或光刺激 这表现为在操作会话的早期和晚期阶段响应数量和准确性的减少。在 PFC 中使用选择性 KOR 拮抗剂降二氢托啡肽 (norBNI) 进行局部预处理可在治疗的早期和晚期阻止系统性 KOR 激活的破坏性影响。PFC KORs 的病毒切除阻断了早期而非晚期的破坏,表明突触前和突触后 KORs 在解剖学上可分离。吗啡依赖小鼠的纳洛酮沉淀戒断或光刺激 提示突触前和突触后 KOR 在解剖学上可分离的贡献。吗啡依赖小鼠的纳洛酮沉淀戒断或光刺激 提示突触前和突触后 KOR 在解剖学上可分离的贡献。吗啡依赖小鼠的纳洛酮沉淀戒断或光刺激使用 Channelrhodopsin-2 的pdyn Cre神经元破坏了延迟交替性能,强啡肽诱导的作用被局部 norBNI 阻断。我们的研究结果描述了一种在阿片类药物依赖期间控制皮质功能的机制,并表明 KOR 拮抗作用可以促进戒断。

更新日期:2021-09-21
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