Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis.
Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis.
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DOI：
10.1016/j.neuropharm.2018.07.034
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发表时间：
2018-09-15
影响因子：
4.7
通讯作者：
Walker BM
中科院分区：
文献类型：
--
作者：
Erikson CM;Wei G;Walker BM
内源性阿片强啡肽（DYN）和κ阿片受体（KOR）在酒精依赖治疗中的重要作用日益显现。有证据表明DYN/KOR系统在终纹床核（BNST）中与酒精依赖和戒断相关的适应不良行为调节中的作用。目前的实验旨在通过评估酒精依赖诱导的DYN/KOR基因表达（分别为Pdyn和Oprk 1）的变化，以及酒精自我给药、负性情感样行为和生理性戒断对急性戒断期间BNST KOR内拮抗作用的敏感性，来评估BNST DYN/KOR系统的失调。训练或未训练的Wistar大鼠接受酒精依赖诱导程序（14小时酒精蒸汽/10小时空气）或空气暴露。使用RT-qPCR分析来自空气和蒸汽暴露动物的BNST微穿孔，以量化依赖性诱导的Pdyn和Oprk 1 mRNA表达变化。此外，蒸汽和空气暴露组在测量酒精自我给药前接受KOR拮抗剂或溶剂的BNST内输注。在BNST内KOR拮抗作用后，评估了一组单独的蒸汽暴露大鼠的生理性戒断和负面情感样行为体征。在急性戒断，酒精依赖诱导后，有一个上调Oprk 1基因表达的酒精自我管理的动物，但不非酒精自我管理的动物，证实失调的KOR/DYN系统内的BNST。此外，BNST KOR内拮抗作用减弱了急性戒断期间酒精自我给药和负面情感样行为的增加，而不会可靠地影响戒断的生理症状。结果证实了酒精依赖BNST中KOR系统的失调，说明了靶向KOR治疗酒精依赖的治疗潜力。
There is an important emerging role for the endogenous opioid dynorphin (DYN) and the kappa-opioid receptor (KOR) in the treatment of alcohol dependence. Evidence suggests a role for the DYN/KOR system in the bed nucleus of the stria terminalis (BNST) in maladaptive behavioral regulation related to alcohol dependence and withdrawal. The current experiments were designed to assess dysregulation of the BNST DYN/KOR system by evaluating alcohol dependence-induced changes in DYN/KOR gene expression (Pdyn and Oprk1, respectively), and the sensitivity of alcohol self-administration, negative affective-like behavior and physiological withdrawal to intra-BNST KOR antagonism during acute withdrawal. Wistar rats trained to self-administer alcohol, or not trained, were subjected to an alcohol dependence induction procedure (14h alcohol vapor /10h air) or air-exposure. BNST micropunches from airand vapor-exposed animals were analyzed using RT-qPCR to quantify dependence-induced changes in Pdyn and Oprk1 mRNA expression. In addition, vapor- and air-exposed groups received an intra-BNST infusion of a KOR antagonist or vehicle prior to measurement of alcohol self-administration. A separate cohort of vapor-exposed rats was assessed for physiological withdrawal and negative affective-like behavior signs following intra-BNST KOR antagonism. During acute withdrawal, following alcohol dependence induction, there was an upregulation in Oprk1 gene expression in alcohol self-administering animals, but not non-alcohol self-administering animals, that confirmed dysregulation of the KOR/DYN system within the BNST. Furthermore, intra-BNST KOR antagonism attenuated escalated alcohol self-administration and negative affective-like behavior during acute withdrawal without reliably impacting physiological symptoms of withdrawal. The results confirm KOR system dysregulation in the BNST in alcohol dependence, illustrating the therapeutic potential of targeting the KOR to treat alcohol dependence.
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