Department of Physiology, Louisiana State University, Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70130, USA.
Committee on the Neurobiology of Addictive Disorders & Pearson Center for Alcoholism and Addiction Research, SP30 2400, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuropharmacology. 2014 Feb;77:294-302. doi: 10.1016/j.neuropharm.2013.10.005. Epub 2013 Oct 21.
Activation of the kappa opioid receptor (KOR) system mediates negative emotional states and considerable evidence suggests that KOR and their natural ligand, dynorphin, are involved in ethanol dependence and reward. The central amygdala (CeA) plays a major role in alcohol dependence and reinforcement. Dynorphin peptide and gene expression are activated in the amygdala during acute and chronic administration of alcohol, but the effects of activation or blockade of KOR on inhibitory transmission and ethanol effects have not been studied. We used the slice preparation to investigate the physiological role of KOR and interaction with ethanol on GABA(A) receptor-mediated synaptic transmission. Superfusion of dynorphin or U69593 onto CeA neurons decreased evoked inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the KOR antagonist norbinaltorphimine (norBNI). Applied alone, norBNI increased GABAergic transmission, revealing a tonic endogenous activity at KOR. Paired-pulse analysis suggested a presynaptic KOR mechanism. Superfusion of ethanol increased IPSPs and pretreatment with KOR agonists diminished the ethanol effect. Surprisingly, the ethanol-induced augmentation of IPSPs was completely obliterated by KOR blockade. Our results reveal an important role of the dynorphin/KOR system in the regulation of inhibitory transmission and mediation of ethanol effects in the CeA.
κ 阿片受体（KOR）系统的激活介导了负面情绪状态，大量证据表明，KOR 及其天然配体强啡肽与乙醇依赖和奖赏有关。中央杏仁核（CeA）在酒精依赖和强化中起主要作用。在急性和慢性给予酒精时，杏仁核中的强啡肽肽和基因表达被激活，但 KOR 的激活或阻断对抑制性传递和乙醇作用的影响尚未研究。我们使用切片制备来研究 KOR 的生理作用以及与乙醇的相互作用对 GABA(A) 受体介导的突触传递的影响。将 dynorphin 或 U69593 超注入 CeA 神经元以浓度依赖性方式减少诱发的抑制性突触后电位（IPSPs），该作用可被 KOR 拮抗剂 norbinaltorphimine（norBNI）阻止。单独应用时，norBNI 增加 GABA 能传递，揭示了 KOR 的紧张内源性活性。成对脉冲分析表明存在突触前 KOR 机制。乙醇的超注入增加了 IPSPs，而 KOR 激动剂的预处理则减弱了乙醇的作用。令人惊讶的是，KOR 阻断完全消除了乙醇诱导的 IPSPs 增强。我们的结果揭示了 dynorphin/KOR 系统在调节 CeA 中的抑制性传递和介导乙醇作用中的重要作用。
