van der Hart Marieke G C, de Biurrun Gabriel, Czéh Boldizsár, Rupniak Nadia M J, den Boer Johan A, Fuchs Eberhard
Clinical Neurobiology Laboratory, German Primate Center, Göttingen.
Psychopharmacology (Berl). 2005 Sep;181(2):207-16. doi: 10.1007/s00213-005-2260-0. Epub 2005 Oct 14.
Substance P and its preferred receptor, the neurokinin 1 receptor (NK(1)R), have been proposed as possible targets for new antidepressant therapies, although results of a recently completed phase III trial failed to demonstrate that the NK(1)R antagonist MK-869 is more effective than placebo in the treatment of depression.
In the present study, we compared the effects of the NK(1)R antagonist L-760735 with the tricyclic antidepressant clomipramine on endocrine and behavioral parameters in chronically stressed tree shrews. Animals were subjected to a 7-day period of psychosocial stress before receiving daily oral administration of L-760735 (10 mg/kg/day) or clomipramine (50 mg/kg/day). The psychosocial stress continued throughout the treatment period of 21 days. Daily morning urine was collected to measure cortisol and norepinephrine levels. All animals were videotaped daily and three types of behavior were analyzed.
Chronic psychosocial stress resulted in a significant increase of urinary cortisol and norepinephrine concentrations. Moreover, stressed animals displayed decreased marking behavior and locomotor activity, while grooming remained unaffected. Neither treatment with clomipramine nor L-760735 was able to normalize the stress-induced elevation of cortisol or norepinephrine. On the behavioral parameters, L-760735 had a time-dependent restorative influence on marking behavior close to normal levels, without affecting locomotor activity. Grooming behavior was significantly increased by the 3 weeks of drug treatment.
These results suggest that L-760735 was able to counteract certain stress-induced behavioral alterations in an animal model of depression.
尽管最近完成的一项III期试验结果未能证明神经激肽1受体（NK(1)R）拮抗剂MK-869在治疗抑郁症方面比安慰剂更有效，但P物质及其首选受体神经激肽1受体（NK(1)R）已被提议作为新型抗抑郁疗法的可能靶点。
在本研究中，我们比较了NK(1)R拮抗剂L-760735与三环类抗抑郁药氯米帕明对慢性应激树鼩内分泌和行为参数的影响。在每天口服给予L-760735（10毫克/千克/天）或氯米帕明（50毫克/千克/天）之前，动物先经历7天的社会心理应激。在21天的治疗期内，社会心理应激持续存在。每天早晨收集尿液以测量皮质醇和去甲肾上腺素水平。每天对所有动物进行录像，并分析三种行为类型。
慢性社会心理应激导致尿皮质醇和去甲肾上腺素浓度显著升高。此外，应激动物的标记行为和运动活动减少，而梳理行为未受影响。氯米帕明和L-760735治疗均未能使应激诱导的皮质醇或去甲肾上腺素升高恢复正常。在行为参数方面，L-760735对标记行为有时间依赖性的恢复作用，使其接近正常水平，而不影响运动活动。药物治疗3周后，梳理行为显著增加。
这些结果表明，L-760735能够在抑郁症动物模型中抵消某些应激诱导的行为改变。
