Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core
Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core
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DOI：
10.1007/s00429-018-1805-z
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发表时间：
2019-03-01
影响因子：
3.1
通讯作者：
McGinty, Jacqueline F.
中科院分区：
文献类型：
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作者：
Siemsen, B. M.;Giannotti, G.;McGinty, Jacqueline F.
大鼠自身摄入可卡因（SA）会使前边缘皮质（PrL）的谷氨酸能信号传导失调以及伏隔核（NA）核心的谷氨酸释放异常，从而促进对可卡因的寻求。影响药物寻求复吸的PrL适应性变化在戒断的第一周出现，从早期（2小时）的低谷氨酸能状态转变为后期（7天）的高谷氨酸能状态。在每个时间点使PrL皮质的谷氨酸能信号传导正常化的不同干预措施对于抑制复吸是必要的。我们假设，在投射到伏隔核核心（PrL - NA核心）的PrL皮质神经元戒断的这两个阶段中，调节谷氨酸能神经传递以及树突棘形态的可塑性相关蛋白会受到双相调节。采用一种组合病毒方法，用mCherry荧光报告基因选择性标记PrL - NA核心神经元。雄性大鼠进行2周的可卡因自身摄入或接受共轭盐水输注，并在最后一次自身摄入实验后2小时或7天进行灌注。对第五层PrL - NA核心神经元细胞核中的Fos和pCREB免疫反应性（IR）以及相同神经元顶端树突棘中的GluA1 - IR和GluA2 - IR进行共聚焦显微镜和三维重建分析。在此，我们发现可卡因自身摄入结束2小时后，可卡因自身摄入会降低PrL - NA核心棘头直径、细胞核Fos - IR和pCREB - IR以及假定的蘑菇型棘中的GluA1 - IR和GluA2 - IR，而在戒断1周后情况则相反。我们的研究结果揭示了可卡因自身摄入后PrL - NA核心通路中结构可塑性和复吸相关蛋白的双相、依赖戒断时长的改变。
Cocaine self-administration (SA) in rats dysregulates glutamatergic signaling in the prelimbic (PrL) cortex and glutamate release in the nucleus accumbens (NA) core, promoting cocaine seeking. PrL adaptations that affect relapse to drug seeking emerge during the first week of abstinence, switching from an early (2h) hypoglutamatergic state to a later (7 days) hyperglutamatergic state. Different interventions that normalize glutamatergic signaling in PrL cortex at each timepoint are necessary to suppress relapse. We hypothesized that plasticity-related proteins that regulate glutamatergic neurotransmission as well as dendritic spine morphology would be biphasically regulated during these two phases of abstinence in PrL cortical neurons projecting to the NA core (PrL-NA core). A combinatorial viral approach was used to selectively label PrL-NA core neurons with an mCherry fluorescent reporter. Male rats underwent 2weeks of cocaine SA or received yoked-saline infusions and were perfused either 2h or 7 days after the final SA session. Confocal microscopy and 3D reconstruction analyses were performed for Fos and pCREB immunoreactivity (IR) in the nucleus of layer V PrL-NA core neurons and GluA1-IR and GluA2-IR in apical dendritic spines of the same neurons. Here, we show that cocaine SA decreased PrL-NA core spine head diameter, nuclear Fos-IR and pCREB-IR, and GluA1-IR and GluA2-IR in putative mushroom-type spines 2h after the end of cocaine SA, whereas the opposite occurred following 1week of abstinence. Our findings reveal biphasic, abstinence duration-dependent alterations in structural plasticity and relapse-related proteins in the PrL-NA core pathway after cocaine SA.