Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala κ-Opioid Receptors
Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala κ-Opioid Receptors
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DOI：
10.1038/npp.2015.183
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发表时间：
2016-01-01
影响因子：
7.6
通讯作者：
Walker, Brendan M.
中科院分区：
文献类型：
--
作者：
Kissler, Jessica L.;Walker, Brendan M.
慢性间歇性酒精蒸汽暴露导致强啡肽（DYN）A样肽表达增加和杏仁核（CeA）中央核中κ-阿片受体（KOR）信号传导增强，这些神经适应性反应区分酒精依赖性和非依赖性表型。对于治疗开发工作重要的是理解驱动依赖样表型的刺激的性质，例如酒精自我给药的增加。因此，本研究探讨了CeA内KOR拮抗作用对先前暴露于慢性间歇性酒精蒸汽的大鼠在急性戒断和长期戒断期间操作性酒精自我给药和生理性戒断症状升级的影响。在操作训练后，将大鼠植入CeA内导引插管并暴露于长期间歇性酒精蒸汽暴露，导致急性戒断期间酒精自我给药增加和生理戒断体征升高。动物接受CeA内输注的KOR拮抗剂nor-binaltorphimine（nor-BNI; 0，2，4，或6 μ g）之前，操作性酒精自我管理会议和生理性戒断评估急性戒断和长期禁欲。结果表明，在CeA的位点特异性KOR拮抗作用改善了急性戒断和长期禁欲测试期间的酒精自我管理升级，而KOR拮抗作用在任何时间点对生理戒断评分均无影响。这些结果解离升级酒精自我管理与生理戒断症状有关的KOR信号在CeA和帮助澄清刺激的性质，驱动升级酒精自我管理急性戒断和长期禁欲。
Chronic intermittent alcohol vapor exposure leads to increased dynorphin (DYN) A-like peptide expression and heightened kappa-opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA) and these neuroadaptive responses differentiate alcohol-dependent from non-dependent phenotypes. Important for therapeutic development efforts is understanding the nature of the stimulus that drives dependence-like phenotypes such as escalated alcohol self-administration. Accordingly, the present study examined the impact of intra-CeA KOR antagonism on escalated operant alcohol self-administration and physiological withdrawal symptoms during acute withdrawal and protracted abstinence in rats previously exposed to chronic intermittent alcohol vapor. Following operant training, rats were implanted with intra-CeA guide cannula and exposed to long-term intermittent alcohol vapor exposure that resulted in escalated alcohol self-administration and elevated physiological withdrawal signs during acute withdrawal. Animals received intra-CeA infusions of the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 2, 4, or 6 mu g) prior to operant alcohol self-administration sessions and physiological withdrawal assessment during acute withdrawal and protracted abstinence. The results indicated that site-specific KOR antagonism in the CeA ameliorated escalated alcohol self-administration during both acute withdrawal and protracted abstinence test sessions, whereas KOR antagonism had no effect on physiological withdrawal scores at either time point. These results dissociate escalated alcohol self-administration from physiological withdrawal symptoms in relation to KOR signaling in the CeA and help clarify the nature of the stimulus that drives escalated alcohol self-administration during acute withdrawal and protracted abstinence.