Nordquist Rebecca E, Durkin Sean, Jacquet Aurélie, Spooren Will
F Hoffmann-La Roche, Pharma Research Basel Discovery-Neuroscience, Basel, Switzerland.
Eur J Pharmacol. 2008 Dec 14;600(1-3):87-92. doi: 10.1016/j.ejphar.2008.10.011. Epub 2008 Oct 10.
The tachykinin family of receptors has been of strong interest recently due to the potential of the tachykinin NK(3) receptor antagonism in treatment of schizophrenia. However, critical differences in the tachykinin NK(3) receptor between rats, mice and humans make rats and mice less acceptable species for testing tachykinin NK(3) receptor antagonism. This has led to testing of tachykinin NK(3) receptor activity in gerbils and guinea pigs. As these species are much less common laboratory animals than rats and mice, there is a relative paucity of in vivo testing models for tachykinin NK(3) receptor activation. In the present study, locomotor activity induced by the tachykinin NK(3) receptor agonist senktide was characterized. Injection of senktide i.c.v. was found to dose-dependently induce hyperlocomotion from a dose of 0.06 nmol to the maximal dose tested, 0.6 nmol. Locomotion induced by 0.1 nmol of senktide could be blocked by injection of the tachykinin NK(3) receptor antagonists SB222200 (10 and 30 mg/kg i.p.) and talnetant (SB223412; 10 and 30 mg/kg i.p.), as well as by osanetant (SR142801; 10 and 30 mg/kg i.p.) when administered in a vehicle containing vitamin E and glycofurol. Senktide-induced activity was also reversed by the antipsychotics haloperidol (0.3 and 1 mg/kg p.o.) and risperidone (1 mg/kg p.o.), but not by the serotonin 5HT(2a/c) receptor antagonist MDL100907 (tested at 0.1, 0.3 and 1 mg/kg p.o.). Hyperlocomotion induced by 0.03 nmol of senktide was potentiated by antagonism of the tachykinin NK(1) receptor with aprepitant (1, 3 and 10 mg/kg, p.o.). Thus, hyperlocomotion induced by senktide in gerbils is a tachykinin NK(3) receptor-mediated behavior that is appropriate for use in testing tachykinin NK(3) receptor activity of novel compounds.
由于速激肽NK(3)受体拮抗剂在治疗精神分裂症方面的潜力，速激肽受体家族最近引起了人们的强烈关注。然而，大鼠、小鼠和人类的速激肽NK(3)受体存在关键差异，这使得大鼠和小鼠作为测试速激肽NK(3)受体拮抗剂的实验动物不太理想。这导致了在沙鼠和豚鼠中对速激肽NK(3)受体活性进行测试。由于这些物种作为实验动物比大鼠和小鼠少见得多，因此用于速激肽NK(3)受体激活的体内测试模型相对较少。在本研究中，对速激肽NK(3)受体激动剂senktide诱导的运动活性进行了表征。发现脑室内注射senktide可剂量依赖性地诱导运动亢进，剂量范围从0.06 nmol到测试的最大剂量0.6 nmol。注射0.1 nmol的senktide所诱导的运动可被注射速激肽NK(3)受体拮抗剂SB222200（10和30 mg/kg腹腔注射）、talnetant（SB223412；10和30 mg/kg腹腔注射）以及osanetant（SR142801；10和30 mg/kg腹腔注射）阻断，这些拮抗剂均以含有维生素E和甘氨胆醇的载体给药。senktide诱导的活性也可被抗精神病药物氟哌啶醇（0.3和1 mg/kg口服）和利培酮（1 mg/kg口服）逆转，但不能被5-羟色胺5HT(2a/c)受体拮抗剂MDL100907（0.1、0.3和1 mg/kg口服测试）逆转。用阿瑞匹坦（1、3和10 mg/kg，口服）拮抗速激肽NK(1)受体可增强0.03 nmol的senktide所诱导的运动亢进。因此，senktide在沙鼠中诱导的运动亢进是一种速激肽NK(3)受体介导的行为，适用于测试新型化合物的速激肽NK(3)受体活性。
