Mu Ping, Neumann Peter A, Panksepp Jaak, Schlüter Oliver M, Dong Yan
Washington State University, Pullman, USA.
Biol Psychiatry. 2011 Feb 1;69(3):228-35. doi: 10.1016/j.biopsych.2010.09.014. Epub 2010 Oct 27.
Dysregulation of excitatory synaptic input to nucleus accumbens (NAc) medium spiny neurons (MSNs) underlies a key pathophysiology of drug addiction and addiction-associated emotional and motivational alterations. Dynorphin peptides, which exhibit higher affinity to κ type opioid receptors, are upregulated within the NAc upon exposure to cocaine administration, and the increased dynorphin-signaling in the NAc has been critically implicated in negative mood observed in cocaine- or stress-exposed animals. Despite such apparent behavioral significance of the NAc dynorphins, the understanding of how dynorphins regulate excitatory synaptic transmission in the NAc remains incomplete.
We used electrophysiological recording in brain slices to examine the effects of dynorphins on excitatory synaptic transmission in the NAc.
We focused on two key dynorphins, dynorphin A and B. Our current results show that dynorphin A and B differentially regulated excitatory postsynaptic currents (EPSCs) in NAc MSNs. Whereas perfusions of both dynorphin A and B to NAc slices decreased EPSCs in MSNs, the effect of dynorphin A but not dynorphin B was completely reversed by the κ receptor-selective antagonist nor-binaltorphimine. These results implicate κ receptor-independent mechanisms in dynorphin B-mediated synaptic effects in the NAc. Furthermore, repeated exposure to cocaine (15 mg/kg/day via intraperitoneal injection for 5 days, with 1, 2, or 14 days withdrawal) completely abolished dynorphin A-mediated modulation of EPSCs in NAc MSNs, whereas the effect of dynorphin B remained largely unchanged.
Given the quantitatively higher abundance of dynorphin B in the NAc, our present results suggest that the dynorphin B-mediated, κ receptor-independent pathways predominate in the overall effect of dynorphins in cocaine-pretreated animals and potentially in cocaine-induced alterations in mood.
伏隔核（NAc）中棘神经元（MSNs）兴奋性突触输入的失调是药物成瘾以及成瘾相关的情绪和动机改变的关键病理生理学基础。强啡肽对κ型阿片受体具有更高的亲和力，在给予可卡因后，NAc内的强啡肽会上调，并且NAc中强啡肽信号的增加与在可卡因暴露或应激动物中观察到的负面情绪密切相关。尽管NAc强啡肽具有如此明显的行为学意义，但对强啡肽如何调节NAc中的兴奋性突触传递的理解仍不完整。
我们使用脑片电生理记录来研究强啡肽对NAc中兴奋性突触传递的影响。
我们聚焦于两种关键的强啡肽，强啡肽A和强啡肽B。我们目前的结果表明，强啡肽A和强啡肽B对NAc MSNs中的兴奋性突触后电流（EPSCs）有不同的调节作用。虽然将强啡肽A和强啡肽B灌注到NAc切片中均会降低MSNs中的EPSCs，但κ受体选择性拮抗剂 nor - binaltorphimine可完全逆转强啡肽A而非强啡肽B的作用。这些结果表明在NAc中，强啡肽B介导的突触效应涉及κ受体非依赖性机制。此外，反复暴露于可卡因（通过腹腔注射，每天15 mg/kg，持续5天，停药1、2或14天）完全消除了强啡肽A介导的对NAc MSNs中EPSCs的调节作用，而强啡肽B的作用基本保持不变。
鉴于NAc中强啡肽B的含量在数量上更高，我们目前的结果表明，在可卡因预处理的动物中，强啡肽B介导的、κ受体非依赖性途径在强啡肽的总体作用中占主导地位，并且可能在可卡因诱导的情绪改变中起作用。
