BACKGROUND Opioid addiction is a critical medical and societal problem characterized by vulnerability to relapse. Glutamatergic synapses in the nucleus accumbens regulate the motivation to relapse to opioid use, and downregulation of glutamate transporters on astroglial processes adjacent to accumbens synapses contributes to heroin seeking induced by cues. However, it is not known how astroglial processes themselves respond to heroin cues or if changes in astroglial morphology are necessary for heroin seeking. METHODS Male Sprague Dawley rats (n = 62) were trained to self-administer heroin or sucrose and were reinstated by heroin-conditioned or sucrose-conditioned cues. Astroglial proximity to accumbens synapses was estimated using a confocal-based strategy, and the association between digitally isolated astroglia and the presynaptic marker synapsin I was quantified. To determine the functional consequence of astroglial morphological plasticity on cued heroin seeking, a morpholino antisense strategy was used to knock down expression of the actin binding protein ezrin, which is expressed almost exclusively in peripheral astroglial processes in the adult rat brain. RESULTS After heroin extinction, there was an enduring reduction in synaptic proximity by astroglia. Synaptic proximity was restored during 15 minutes of cued heroin seeking but returned to extinction levels by 120 minutes. Extinction from sucrose self-administration and reinstated sucrose seeking induced no changes in astroglial synaptic association. Ezrin knockdown reduced astroglial association with synapses and potentiated cued heroin seeking. CONCLUSIONS Cue-induced heroin seeking transiently increased synaptic proximity of accumbens astrocytes. Surprisingly, the reassociation of astroglia with synapses was compensatory, and preventing cue-induced morphological plasticity in astrocytes potentiated heroin seeking.

中文翻译：

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伏隔核突触的海洛因提示诱发的星形胶质细胞结构可塑性抑制海洛因寻找

背景 阿片类药物成瘾是一个严重的医学和社会问题，其特征是易于复发。伏隔核中的谷氨酸能突触调节阿片类药物使用复发的动机，伏隔核突触附近星形胶质细胞过程中谷氨酸转运蛋白的下调有助于线索诱导的海洛因寻找。然而，目前尚不清楚星形胶质细胞过程本身如何对海洛因线索做出反应，或者星形胶质细胞形态的变化是否对寻找海洛因是必要的。方法 雄性 Sprague Dawley 大鼠 (n = 62) 被训练自我给药海洛因或蔗糖，并通过海洛因条件或蔗糖条件提示恢复。使用基于共聚焦的策略估计星形胶质细胞与伏隔突触的接近度，并且量化了数字分离的星形胶质细胞和突触前标记突触蛋白 I 之间的关联。为了确定星形胶质细胞形态可塑性对线索海洛因寻找的功能后果，使用吗啉代反义策略来抑制肌动蛋白结合蛋白 ezrin 的表达，该蛋白几乎只在成年大鼠大脑的外周星形胶质细胞过程中表达。结果 海洛因灭绝后，星形胶质细胞的突触接近度持续降低。在 15 分钟的提示海洛因寻找期间，突触接近性恢复，但在 120 分钟后恢复到灭绝水平。蔗糖自我管理的灭绝和恢复蔗糖寻求诱导星形胶质细胞突触协会没有变化。Ezrin 敲除减少了星形胶质细胞与突触的关联，并增强了海洛因寻找线索。结论提示诱导的海洛因寻求瞬时增加伏隔星形胶质细胞的突触接近度。令人惊讶的是，星形胶质细胞与突触的重新关联是补偿性的，并且防止星形胶质细胞中提示诱导的形态可塑性增强了海洛因寻求。