Czéh Boldizsár, Pudovkina Olga, van der Hart Marieke G C, Simon Mária, Heilbronner Urs, Michaelis Thomas, Watanabe Takashi, Frahm Jens, Fuchs Eberhard
Clinical Neurobiology Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany.
Psychopharmacology (Berl). 2005 Jul;180(3):548-57. doi: 10.1007/s00213-005-2184-8. Epub 2005 Feb 22.
Substance P antagonists have been proposed as candidates for a new class of antidepressant compounds.
We examined the effects of SLV-323, a novel neurokinin 1 receptor (NK1R) antagonist, in the chronic psychosocial stress paradigm of adult male tree shrews.
Animals were subjected to a 7 day period of psychosocial stress before being treated daily with SLV-323 (20 mg kg(-1) day(-1)). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Norepinephrine excretion was monitored from daily urine samples, and serum testosterone concentrations were measured at the end of the experiment. All animals were videotaped daily to analyze scent-marking behavior and locomotor activity. Cell proliferation in the dentate gyrus and hippocampal volume were measured postmortem.
Stress significantly decreased cerebral concentrations of N-acetyl-aspartate, total creatine, and choline-containing compounds in vivo and resulted in an increase of urinary norepinephrine and decrease of serum testosterone concentrations. Moreover, stressed animals displayed decreased scent-marking behavior and locomotor activity. The proliferation rate of the granule precursor cells in the dentate gyrus was reduced, and hippocampal volume was mildly decreased. The stress-induced alterations in the central nervous system were partially prevented by concomitant administration of SLV-323, while drug treatment had only a minor effect on the stress-induced behavioral changes.
The novel NK1R antagonist SLV-323 has certain antidepressant-like effects in a valid animal model of depression.
P物质拮抗剂已被提议作为一类新型抗抑郁化合物的候选药物。
我们研究了新型神经激肽1受体（NK1R）拮抗剂SLV - 323对成年雄性树鼩慢性社会心理应激模型的影响。
在每天用SLV - 323（20毫克/千克/天）治疗之前，动物先经历7天的社会心理应激。在整个28天的治疗期间，社会心理应激持续存在。通过质子磁共振波谱在体内测定脑代谢物浓度。从每日尿液样本中监测去甲肾上腺素排泄情况，并在实验结束时测量血清睾酮浓度。每天对所有动物进行录像，以分析气味标记行为和运动活动。在死后测量齿状回中的细胞增殖和海马体积。
应激显著降低了体内N - 乙酰天门冬氨酸、总肌酸和含胆碱化合物的脑浓度，并导致尿去甲肾上腺素增加和血清睾酮浓度降低。此外，应激动物的气味标记行为和运动活动减少。齿状回中颗粒前体细胞的增殖率降低，海马体积略有减小。同时给予SLV - 323可部分预防应激诱导的中枢神经系统改变，而药物治疗对应激诱导的行为变化只有轻微影响。
新型NK1R拮抗剂SLV - 323在有效的抑郁症动物模型中具有一定的抗抑郁样作用。
