Dysregulated kappa-opioid receptors in the medial prefrontal cortex contribute to working memory deficits in alcohol dependence.
Dysregulated kappa-opioid receptors in the medial prefrontal cortex contribute to working memory deficits in alcohol dependence.
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DOI：
10.1111/adb.13138
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发表时间：
2022-03
影响因子：
3.4
通讯作者：
Walker BM
中科院分区：
文献类型：
--
作者：
Wei G;Sirohi S;Walker BM
工作记忆受损是酒精使用障碍（AUD）中导致执行功能受损的一种症状。皮质强啡肽（DYN）和κ-阿片受体（KORs）的失调与酒精依赖诱导的执行功能障碍有关。本实验验证了内侧前额叶皮质（mPFC）KOR失调有助于酒精依赖的工作记忆受损的假设。通过4个月的间歇性乙醇蒸汽暴露之前，在mPFC依赖性工作记忆任务（延迟非匹配到样本任务; DNMST）的训练/测试诱导酒精依赖的雄性Wistar大鼠。使用DYNA刺激的[35 S]GTPγS偶联试验，比较了酒精初治大鼠、酒精依赖和非依赖大鼠的mPFC KOR功能。在DNMST评估之前，通过mPFC内输注KOR激动剂评估mPFC KOR在工作记忆调节中的功能作用，并通过mPFC输注KOR拮抗剂norbinaltorphimine（nor-BNI）评估mPFC KOR对依赖性工作记忆受损的贡献。在酒精依赖大鼠中，DNMST的表现受损证实了工作记忆受损。此外，DYNA刺激的mPFC KOR功能在酒精依赖大鼠中病理性增加，与非依赖和酒精初治大鼠相比。此外，mPFC KOR参与工作记忆的功能通过mPFC KOR内激动剂诱导的DNMST表现缺陷得到证实。重要的是，酒精依赖诱导的DNMST损伤可通过mPFC内KOR拮抗作用得到改善。通过mPFC KOR调节工作记忆和酒精依赖诱导的mPFC KOR功能失调确定了治疗工作记忆障碍的AUD相关症状的新治疗靶点。
Impaired working memory is one symptom contributing to compromised executive function in alcohol use disorder (AUD). Dysregulation of cortical dynorphin (DYN) and κ-opioid receptors (KORs) has been implicated in alcohol dependence-induced impairment in executive function. The present experiments test the hypothesis that dysregulated medial prefrontal cortex (mPFC) KORs contribute to impaired working memory in alcohol dependence. Alcohol dependence was induced in male Wistar rats via four months of intermittent ethanol vapor exposure prior to training / testing in an mPFC-dependent working memory task (delayed nonmatching-to-sample task; DNMST). mPFC KOR function in alcohol-naïve rats was compared to that of alcohol-dependent and non-dependent rats using a DYN A-stimulated [35S]GTPγS coupling assay. A functional role for mPFC KORs in the regulation of working memory was assessed via intra-mPFC infusions of a KOR agonist prior to assessment in the DNMST and the contribution of mPFC KORs to compromised working memory in dependence was assessed via mPFC infusions of the KOR antagonist norbinaltorphimine (nor-BNI). In alcohol-dependent rats, impaired performance in the DNMST confirmed compromised working memory. Furthermore, DYN A-stimulated mPFC KOR function was pathologically increased in alcohol-dependent rats compared to non-dependent and alcohol-naïve rats. Additionally, mPFC KOR involvement in working memory was functionally confirmed by intra-mPFC KOR agonist-induced deficits in DNMST performance. Importantly, alcohol dependence-induced impairment in the DNMST was ameliorated by intra-mPFC KOR antagonism. Regulation of working memory by mPFC KORs and alcohol dependence-induced dysregulation of mPFC KOR function identify a novel therapeutic target to treat AUD-related symptoms of working memory impairment.
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影响因子：
8.2
作者：
George, Olivier;Koob, George F.
通讯作者：
Koob, George F.
酒精中毒的一二拳：中央杏仁核的作用/kappa-阿片受体。
影响因子：
10.6
作者：
Kissler, Jessica L.;Sirohi, Sunil;Reis, Daniel J.;Jansen, Heiko T.;Quock, Raymond M.;Smith, Daniel G.;Walker, Brendan M.
通讯作者：
Walker, Brendan M.
影响因子：
3.4
作者：
Bazov, Igor;Kononenko, Olga;Bakalkin, Georgy
通讯作者：
Bakalkin, Georgy
影响因子：
2.3
作者：
Gunn, Rachel L.;Finn, Peter R.
通讯作者：
Finn, Peter R.
影响因子：
7.6
作者：
Kissler, Jessica L.;Walker, Brendan M.
通讯作者：
Walker, Brendan M.