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

对非人类灵长类动物大脑中速激肽受体的研究将有助于阐明速激肽系统在情感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（称为rmNK-1和rmNK-3）的基因，并研究了它们的药理学特征和在CNS中的区域分布。配体结合研究表明，在稳定表达单个受体的细胞系中，rmNK-1对P物质（SP）的亲和力与hNK-1相当。rmNK-1的表达在所有的皮质和皮质下区域，包括海马和杏仁核。壳核含有脑中最多的NK-1 mRNA，与rmNK-1 mRNA相比，在皮质中发现较少的rmNK-3 mRNA。在猴海马和杏仁核中，rmNK-1 mRNA的表达水平显著高于对照组。 ...更多信息 r浓度高于rmNK-3 mRNA。我们研究了实验动物（从啮齿动物到灵长类动物）对使用[^<18>F] fluoroethyl-SPA-RQ（最近建立的NK-1受体放射性配体的修饰）进行正电子发射断层扫描（PET）测量的适用性。可以在清醒状态下对恒河猴进行药代动力学测定，这允许规避麻醉对SP神经传递的影响。通过小动物专用设备获得的PET和磁共振图像的配准，可以详细定位沙鼠和绒猴大脑中的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。结合额外的体外和离体放射自显影观察，我们的体内结果已经证明了所检查的动物之间的结合模式的相似性，证明了SP-NK-1途径的PET结果的跨物种外推。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