The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors.
The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors.
复制标题
酒精中毒的一二拳：中央杏仁核的作用/kappa-阿片受体。
DOI：
10.1016/j.biopsych.2013.03.014
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发表时间：
2014-05-15
影响因子：
10.6
通讯作者：
Walker, Brendan M.
中科院分区：
文献类型：
--
作者：
Kissler, Jessica L.;Sirohi, Sunil;Reis, Daniel J.;Jansen, Heiko T.;Quock, Raymond M.;Smith, Daniel G.;Walker, Brendan M.
强啡肽（DYN）/κ-阿片受体（KOR）系统在慢性酒精暴露后经历神经适应，促进过度的操作性自我管理和负性情感样状态;然而，确切的机制尚不清楚。本研究通过评估DYN A肽表达和KOR功能，结合位点特异性药理学操作，检验了上调的DYN/KOR系统介导酒精依赖大鼠戒断期间发生的过量酒精自我给药的假设。雄性Wistar大鼠接受训练，自我管理酒精使用操作性行为策略和间歇性酒精蒸汽或空气暴露。通过急性戒断期间的药理学激发评估自我给药的变化。此外，22 kHz的超声波发声被用来测量消极的情感样状态。免疫组化技术评估DYNA肽表达，[35 S] GTP γ S偶联试验评估KOR功能。与非依赖性对照组相比，酒精依赖大鼠杏仁核中的酒精自我给药、负性情感样行为、DYNA样免疫反应性和KOR信号传导增加。位点特异性输注KOR拮抗剂选择性地减弱依赖性大鼠的自我给药，而莫尔/DOR拮抗剂鸡尾酒选择性地减少非依赖性大鼠的自我给药。莫尔拮抗剂/部分KOR激动剂减弱了两个队列中的自我给药。增加DYNA和增加KOR信号可以为戒断过程中的“一击两拳”奠定基础，从而驱动酒精依赖中的过度饮酒。重要的是，内CeA药理学挑战功能上证实了DYN/KOR系统参与酒精自我管理的升级。总之，DYN/KOR系统在酒精依赖中严重失调，并导致戒断期间过量饮酒。
The dynorphin (DYN)/κ-opioid receptor (KOR) system undergoes neuroadaptations following chronic alcohol exposure that promote excessive operant self-administration and negative affective-like states; however, the exact mechanisms are unknown. The present studies tested the hypothesis that an upregulated DYN/KOR system mediates excessive alcohol self-administration that occurs during withdrawal in alcohol-dependent rats by assessing DYN A peptide expression and KOR function, in combination with site-specific pharmacological manipulations. Male Wistar rats were trained to self-administer alcohol using operant behavioral strategies and subjected to intermittent alcohol vapor- or air-exposure. Changes in self-administration were assessed by pharmacological challenges during acute withdrawal. In addition, 22-kHz ultrasonic vocalizations were utilized to measure negative affective-like states. Immunohistochemical techniques assessed DYN A peptide expression and [35S]GTPγS coupling assays were performed to assess KOR function. Alcohol-dependent rats displayed increased alcohol self-administration, negative affective-like behavior, DYN A-like immunoreactivity and KOR signaling in the amygdala compared to non-dependent controls. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats whereas, a MOR/DOR antagonist cocktail selectively reduced self-administration in non-dependent rats. A MOR antagonist/partial KOR agonist attenuated self-administration in both cohorts. Increased DYN A and increased KOR signaling could set the stage for a `one-two punch' during withdrawal that drives excessive alcohol consumption in alcohol-dependence. Importantly, intra-CeA pharmacological challenges functionally confirmed a DYN/KOR system involvement in the escalated alcohol self-administration. Together, the DYN/KOR system is heavily dysregulated in alcohol dependence and contributes to the excessive alcohol consumption during withdrawal.
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影响因子：
4.3
作者：
Koob GF
通讯作者：
Koob GF
影响因子：
3.6
作者：
Deehan, Gerald A., Jr.;McKinzie, David L.;Rodd, Zachary A.
通讯作者：
Rodd, Zachary A.
影响因子：
3.4
作者：
Bazov, Igor;Kononenko, Olga;Bakalkin, Georgy
通讯作者：
Bakalkin, Georgy
影响因子：
5.5
作者：
Bouchery, Ellen E.;Harwood, Henrick J.;Brewer, Robert D.
通讯作者：
Brewer, Robert D.
影响因子：
2.3
作者：
Lindholm, S;Ploj, K;Nylander, I
通讯作者：
Nylander, I