Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla CA, USA ; Pharmacology Unit, School of Pharmacy, University of Camerino Camerino, Italy.
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla CA, USA.
Front Integr Neurosci. 2014 Feb 18;8:18. doi: 10.3389/fnint.2014.00018. eCollection 2014.
The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. A large body of evidence shows that Nociceptin/Orphanin FQ (N/OFQ) regulates ethanol intake and anxiety-like behavior. In the rat, ethanol significantly augments CeA GABA release, whereas N/OFQ diminishes it. Using electrophysiological techniques in an in vitro slice preparation, in this study we investigated the effects of a nonpeptidergic NOP receptor agonist, MT-7716 [(R)-2-3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl-N-methylacetamide hydrochloride hydrate], and its interaction with ethanol on GABAergic transmission in CeA slices of naïve rats. We found that MT-7716 dose-dependently (100-1000 nM) diminished evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) and increased paired-pulse facilitation (PPF) ratio of these evoked IPSPs, suggesting a presynaptic site of action of the MT-7716 by decreasing GABA release at CeA synapses. The presynaptic action of MT-7716 was also supported by the significant decrease in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) induced by the nociceptin receptor (NOP) agonist. Interestingly, MT-7716 prevented the ethanol-induced augmentation of evoked IPSPs. A putative selective NOP antagonist, [Nphe1]Nociceptin(1-13)NH2, totally prevented the MT-7716-induced inhibition of IPSP amplitudes indicating that MT-7716 exerts its effect through NOPs. These data provide support for an interaction between the nociceptin and GABAergic systems in the CeA and for the anti-alcohol properties of the NOP activation. The development of a synthetic nonpeptidergic NOP receptor agonist such as MT-7716 may represent a useful therapeutic target for alcoholism.
中央杏仁核（CeA）中的 GABA 能系统在乙醇依赖和乙醇戒断时的焦虑样反应中起着重要作用。大量证据表明，孤啡肽/孤啡肽（N/OFQ）调节乙醇摄入和焦虑样行为。在大鼠中，乙醇显著增强 CeA GABA 释放，而 N/OFQ 则减少它。在体外切片制备中使用电生理技术，在这项研究中，我们研究了非肽 NOP 受体激动剂 MT-7716 [（R）-2-3-[1-（十氢萘-1-基）哌啶-4-基]-2-氧代-2,3-二氢-1H-苯并咪唑-1-基-N-甲基乙酰胺盐酸盐水合物]及其与乙醇对 Naive 大鼠 CeA 切片 GABA 能传递的相互作用。我们发现，MT-7716 剂量依赖性（100-1000 nM）减弱了诱发的 GABAA 受体介导的抑制性突触后电位（IPSP），并增加了这些诱发 IPSP 的成对脉冲易化（PPF）比值，表明 MT-7716 的作用部位是通过减少 CeA 突触 GABA 的释放。MT-7716 的这种突触前作用也得到了以下事实的支持：Nociceptin 受体（NOP）激动剂诱导的微小抑制性突触后电流（mIPSCs）的频率显著降低。有趣的是，MT-7716 阻止了乙醇诱导的 IPSP 增强。一种假定的选择性 NOP 拮抗剂[Nphe1]Nociceptin（1-13）NH2 完全阻止了 MT-7716 诱导的 IPSP 幅度抑制，表明 MT-7716 通过 NOP 发挥作用。这些数据为 CeA 中孤啡肽和 GABA 能系统之间的相互作用以及 NOP 激活的抗酒精特性提供了支持。合成非肽 NOP 受体激动剂如 MT-7716 的开发可能代表治疗酒精中毒的有用治疗靶点。
