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

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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