α2δ-1 Signaling in Nucleus Accumbens Is Necessary for Cocaine-Induced Relapse
α2δ-1 Signaling in Nucleus Accumbens Is Necessary for Cocaine-Induced Relapse
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DOI：
10.1523/jneurosci.1204-13.2014
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发表时间：
2014-06-18
影响因子：
5.3
通讯作者：
Kalivas, Peter W.
中科院分区：
文献类型：
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作者：
Spencer, Sade;Brown, Robyn M.;Kalivas, Peter W.
可卡因寻求复发与脑桥核兴奋性突触增强有关。alpha（2）delta-1是电压门控钙通道的辅助亚基，影响钙通道运输和动力学，启动细胞外信号级联，并促进兴奋性突触发生。先前的数据表明，反复接触酒精、尼古丁、甲基苯丙胺和吗啡会上调与奖励相关的大脑区域中的α 2 δ-1，但尚不清楚这种改变是否普遍适用于可卡因。在这里，我们表明，α（2）δ-1蛋白增加后，可卡因自我管理和灭绝与盐水对照组相比，在延髓核。此外，负责α（2）δ-1受体突触形成特性的内源性配体血小板反应蛋白-1也同样升高。使用全细胞膜片钳记录的EPSCs在延髓核，我们证明，加巴喷丁，一个特定的α（2）δ-1拮抗剂，优先降低振幅和增加成对脉冲比的电刺激诱发的EPSCs从可卡因经验的大鼠与对照组相比。在体内，加巴喷丁微量注射在延髓核核心衰减可卡因引发，但没有线索诱导的恢复。重要的是，加巴喷丁对药物寻求的影响并不是由于自发或可卡因诱导的运动活动的普遍抑制。此外，加巴喷丁对恢复蔗糖寻求没有影响。这些数据表明，alpha（2）delta-1特别有助于可卡因复吸的药物寻求，并确定这种蛋白质作为可卡因复吸药物开发的目标。这些结果也通知正在进行的讨论，在文献中关于加巴喷丁作为一个候选成瘾治疗的疗效。
Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. alpha(2)delta-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates alpha(2)delta-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that alpha(2)delta-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the alpha(2)delta-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific alpha(2)delta-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that alpha(2)delta-1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy.