A study on tachykininergic neurotransmission in the primate central nervous system aimed at developing novel drugs against mood disorders

研究非人类灵长类动物大脑中的速激肽受体将有助于阐明速激肽系统在情绪等高级功能中的作用，以及开发治疗情绪障碍的新药。为此，我们进行了以下实验1。我们从恒河猴脑中克隆了编码NK-1和NK-3速激肽受体(简称rmNK-1和rmNK-3)的基因，并研究了它们在中枢神经系统的药理特征和区域分布。配体结合研究表明，在稳定表达单个受体的细胞系中，rmNK-1与P物质(SP)的亲和力与HNK-1相当。RmNK-1在所有皮质和皮质下区域均有表达，包括海马区和杏仁体。与rmNK-1mRNA相比，壳核在大脑中含有最多的NK-1mRNA，而在皮质中发现的rmNK-3mRNA较少。在猴的海马体和杏仁核中，rmnk-1mrna在…显著升高。R浓度高于rmNK-3mRNA2。我们调查了实验动物，从啮齿动物到灵长类动物，到正电子发射断层扫描(PET)测量的适用性，使用[^&lt；18&gt；F]氟乙基-SPA-RQ，这是最近建立的NK-1受体放射性配体的改进。在清醒状态下，可以对恒河猴进行药代动力学分析，这允许避开麻醉对SP神经传递的影响。通过小动物专用设备获取的PET和磁共振图像的共同配准，可以在沙鼠和绒猴的大脑中详细定位NK-1受体。本研究还揭示了SDZ NKT 343作为中枢NK-1受体拮抗剂的潜力。结合额外的体外和体外放射自显影观察，我们在体内的结果表明，在所研究的动物之间的结合模式相似，证明了跨物种外推的PET发现的SP-NK-1途径。较少

Research of tachykinin receptors in the non-human primate brain would be useful for elucidating the role of the tachykinin system in higher functions such as emotion, as well as for developing new drugs against mood disorders. To this end, we performed the following experiments.1. We cloned the genes encoding the NK-1 and NK-3 tachykinin receptors (referred to as rmNK-1 and rmNK-3) from the rhesus monkey brain and examined their pharmacological profiles and regional distributions in the CNS. Ligand binding studies revealed that the affinity of rmNK-1 to substance P (SP) was comparable to that of hNK-1 in cell lines that expressed individual receptors stably. The expression of rmNK-1 was observed in all of the cortical and subcortical regions, including the hippocampus and the amygdala. The putamen contained the most NK-1 mRNA in the brain, with less rmNK-3 mRNA found in the cortex compared to rmNK-1 mRNA. In the monkey hippocampus and amygdala, rmNK-1 mRNA was present at markedly highe … More r concentrations than rmNK-3 mRNA.2. We investigated the applicability of experimental animals, ranging from rodents to primates, to positron emission tomographic (PET) measurements with [^<18>F] fluoroethyl-SPA-RQ, a modification of a recently established radioligand for NK-1 receptors. A pharmacokinetic assay could be performed for a rhesus monkey in an awake condition, which allows the circumvention of influences of anesthesia on SP neurotransmission. Coregistration of PET and magnetic resonance images acquired by small-animal-dedicated devices enabled detailed localization of NK-1 receptors in the gerbil and marmoset brains. The present study also revealed the potentials of SDZ NKT 343 as an antagonist for central NK-1 receptors. In conjunction with additional in vitro and ex vivo autoradiographic observations, our in vivo results have demonstrated a similarity in the binding pattern among the animals examined, justifying cross-species extrapolation of PET findings on the SP-NK-1 pathway. Less