Abstract Background Seeking addictive drugs is regulated by synaptic plasticity in the nucleus accumbens core and involves distinct plasticity in D1- and D2-medium spiny neurons (MSNs). However, it is unknown how differential plasticity between the two cell-types is coordinated. Synaptic plasticity and seeking behavior induced by drug-paired cues depends on plasticity not only in the canonical pre- and post-synapse, but also on cue-induced changes in astrocytes and the extracellular matrix adjacent to the synapse. Drug cue-induced signaling in the extracellular matrix is regulated by catalytic activity of matrix metalloproteases-2,9 (MMP-2,9). We hypothesized that the cell-type specific synaptic plasticity is associated with parallel cell-specific activity of MMP-2 and MMP-9. Methods Transgenic rats were trained on a heroin self-administration protocol followed by two weeks of drug withdrawal, and a light/tone cue was paired with heroin delivery. Confocal microscopy was used to make morphological measurements in membrane reporter-transduced D1- and D2-MSNs and astrocytes, and MMP-2,9 gelatinase activity adjacent to cell surfaces was quantified using in vivo zymography. Results Presenting heroin-paired cues transiently increased MMP-9 activity around D1-MSN dendritic spines and synapse-proximal astroglial processes. Conversely, extinction training induced long-lasting increases in MMP-2 activity adjacent to D2-MSN synapses. Moreover, heroin-paired cues increased tissue inhibitor of metalloproteinases-1,2, which caused transient inhibition of MMP-2 activity around D2-MSNs during cue-induced heroin seeking. Conclusions The differential regulation of heroin seeking and and extinguished seeking by different MMP subtypes on distinct cell populations poses MMP-2,9 activity as an important mediator and contributor in heroin-induced cell-specific synaptic plasticity.

中文翻译：

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海洛因寻找和因寻找激活伏隔细胞不同亚群突触处的基质金属蛋白酶而灭绝

摘要 背景 寻求成瘾药物受到伏隔核核心突触可塑性的调节，并涉及 D1 和 D2 中棘神经元 (MSN) 的不同可塑性。然而，尚不清楚这两种细胞类型之间的差异可塑性是如何协调的。药物配对线索诱导的突触可塑性和寻找行为不仅取决于典型的突触前和突触后的可塑性，而且还取决于线索诱导的星形胶质细胞和突触附近的细胞外基质的变化。细胞外基质中药物信号诱导的信号传导受基质金属蛋白酶-2,9 (MMP-2,9) 催化活性的调节。我们假设细胞类型特异性突触可塑性与 MMP-2 和 MMP-9 的平行细胞特异性活性相关。方法 转基因大鼠接受海洛因自我给药方案的训练，然后停药两周，并将光/音提示与海洛因输送配对。使用共聚焦显微镜对膜报告基因转导的 D1-和 D2-MSN 以及星形胶质细胞进行形态学测量，并使用体内酶谱法对细胞表面附近的 MMP-2,9 明胶酶活性进行定量。结果呈现海洛因配对线索会短暂增加 D1-MSN 树突棘和突触近端星形胶质细胞过程周围的 MMP-9 活性。相反，消退训练诱导 D2-MSN 突触附近的 MMP-2 活性持久增加。此外，海洛因配对线索增加了金属蛋白酶-1,2的组织抑制剂，从而在线索诱导的海洛因寻找过程中导致 D2-MSN 周围 MMP-2 活性的短暂抑制。结论 不同 MMP 亚型对不同细胞群对海洛因寻求和消除寻求的差异调节表明 MMP-2,9 活性是海洛因诱导的细胞特异性突触可塑性的重要介质和贡献者。