Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking
Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking
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DOI：
10.1007/s12035-019-01711-9
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发表时间：
2020-01-01
影响因子：
5.1
通讯作者：
Riegel, Arthur C.
中科院分区：
文献类型：
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作者：
Buchta, William C.;Moutal, Aubin;Riegel, Arthur C.
可卡因成瘾仍然是一个主要的健康问题，有效的治疗选择有限。更好地了解复发的机制可能有助于开发新的药物疗法。新出现的证据表明，突触前兴奋性神经递质蛋白2（CRMP 2）调节突触前兴奋性神经传递，并有助于疾病，如神经性疼痛和物质使用障碍的病理变化。我们研究了CRMP 2的作用及其与已知的结合伴侣CaV2.2在可卡因寻求行为中的相互作用。我们采用啮齿类动物自我给药模型的复吸药物寻求和专注于前额叶皮层（PFC），其在复吸行为的作用。我们的研究结果表明，重复可卡因自我管理导致在PFC的表达CRMP 2及其结合伙伴，CaV2.2（N型）电压门控钙通道的动态和持久的改变。在可卡因自我给药和消退训练后，CRMP 2和CaV2.2的表达相对于轭化盐水对照降低。相比之下，暗示恢复增强了CRMP 2表达，并将CaV2.2表达增加到灭绝水平以上。最后，我们利用最近开发的肽myr-TAT-CBD 3来破坏体内CRMP 2和CaV2.2之间的相互作用。我们评估了这种肽直接注入内侧PFC后的恢复行为，发现它减少了线索诱导的可卡因寻求恢复。总之，这些数据表明，PFC中CRMP 2/CaV2.2信号级联的神经适应可以促进药物寻求行为。靶向这种相互作用对可卡因复吸行为的治疗有意义。
Cocaine addiction remains a major health concern with limited effective treatment options. A better understanding of mechanisms underlying relapse may help inform the development of new pharmacotherapies. Emerging evidence suggests that collapsin response mediator protein 2 (CRMP2) regulates presynaptic excitatory neurotransmission and contributes to pathological changes during diseases, such as neuropathic pain and substance use disorders. We examined the role of CRMP2 and its interactions with a known binding partner, CaV2.2, in cocaine-seeking behavior. We employed the rodent self-administration model of relapse to drug seeking and focused on the prefrontal cortex (PFC) for its well-established role in reinstatement behaviors. Our results indicated that repeated cocaine self-administration resulted in a dynamic and persistent alteration in the PFC expression of CRMP2 and its binding partner, the CaV2.2 (N-type) voltage-gated calcium channel. Following cocaine self-administration and extinction training, the expression of both CRMP2 and CaV2.2 was reduced relative to yoked saline controls. By contrast, cued reinstatement potentiated CRMP2 expression and increased CaV2.2 expression above extinction levels. Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo. We assessed the reinstatement behavior after infusing this peptide directly into the medial PFC and found that it decreased cue-induced reinstatement of cocaine seeking. Taken together, these data suggest that neuroadaptations in the CRMP2/CaV2.2 signaling cascade in the PFC can facilitate drug-seeking behavior. Targeting such interactions has implications for the treatment of cocaine relapse behavior.