Protein interacting with C kinase-1 (PICK1) regulates intra-cellular trafficking of GluA2-containing AMPA receptors, a process known to play a critical role in cocaine-seeking behavior. This suggests that PICK1 may represent a molecular target for developing novel pharmacotherapies to treat cocaine craving-induced relapse. Emerging evidence indicates that inhibition of PICK1 attenuates the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we show that systemic administration of TAT-P4-(DATC5)2, a novel high-affinity peptide inhibitor of the PICK1 PDZ domain, dose-dependently attenuated the reinstatement of cocaine seeking in rats at doses that did not produce operant learning deficits or suppress locomotor activity. We also show that systemic TAT-P4-(DATC5)2 penetrated the brain where it was visualized in the nucleus accumbens shell. Consistent with these effects, infusions of TAT-P4-(DATC5)2 directly into the accumbens shell reduced cocaine, but not sucrose, seeking. The effects of TAT-P4-(DATC5)2 on cocaine seeking are likely due, in part, to inhibition of PICK1 in medium spiny neurons (MSNs) of the accumbens shell as TAT-P4-(DATC5)2 was shown to accumulate in striatal neurons and bind PICK1. Taken together, these findings highlight a novel role for PICK1 in the reinstatement of cocaine seeking and support future studies examining the efficacy of peptide inhibitors of PICK1 in animal and human models of cocaine relapse.

中文翻译：

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给予新型高亲和力 PICK1 PDZ 结构域抑制剂可减弱大鼠对可卡因的寻求。


与 C 激酶 1 相互作用的蛋白质 (PICK1) 调节含有 GluA2 的 AMPA 受体的细胞内运输，这一过程已知在可卡因寻求行为中发挥着关键作用。这表明 PICK1 可能代表开发新药物疗法来治疗可卡因渴望引起的复发的分子靶点。新的证据表明，抑制 PICK1 会减弱可卡因寻求行为（一种复发的动物模型）的恢复。在这里，我们发现，全身给予TAT-P4-(DATC5)2（一种PICK1 PDZ结构域的新型高亲和力肽抑制剂），在不产生操作性学习缺陷的剂量下，剂量依赖性地减弱了大鼠对可卡因寻求的恢复。或抑制运动活动。我们还表明，全身 TAT-P4-(DATC5)2 穿透大脑，在伏隔核壳中可见。与这些效果一致，将 TAT-P4-(DATC5)2 直接注入伏隔核中可减少可卡因，但不会减少蔗糖。 TAT-P4-(DATC5)2 对可卡因寻求的影响可能部分归因于伏隔核中型多棘神经元 (MSN) 中 PICK1 的抑制，因为 TAT-P4-(DATC5)2 显示在纹状体神经元并结合 PICK1。总而言之，这些发现强调了 PICK1 在恢复可卡因寻求方面的新作用，并支持未来研究 PICK1 肽抑制剂在可卡因复发的动物和人类模型中的功效。