Peripherally administered non-peptide oxytocin antagonist, L368,899®, accumulates in limbic brain areas:: A new pharmacological tool for the study of social motivation in non-human primates
Peripherally administered non-peptide oxytocin antagonist, L368,899®, accumulates in limbic brain areas:: A new pharmacological tool for the study of social motivation in non-human primates
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DOI：
10.1016/j.yhbeh.2007.05.009
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发表时间：
2007-09-01
影响因子：
3.5
通讯作者：
Pedersen, Cort A.
中科院分区：
文献类型：
--
作者：
Boccia, Maria L.;Goursaud, Anne-Pierre S.;Pedersen, Cort A.
中枢给予催产素拮抗剂可抑制非灵长类动物的母性和性行为，这为内源性催产素促进这些行为提供了最有力的实验证据。虽然有一些报道称，体外注射OT会增加猴子的社会行为，但迄今为止还没有研究评估OT拮抗剂的效果。因此，我们在恒河猴中研究了L368,899(R)，一种默克公司生产的选择性阻断人类子宫OT受体的非肽拮抗剂，是否在外周给药后穿透中枢神经系统并改变雌性母性和性行为。在4只雄性猴子的两项研究中，注射L368,899 (1 mg/kg)，之后(1)每隔4小时收集脑脊液样本，(2)每隔60分钟收集大脑样本。样品分析证实，iv给药L368,899进入脑脊液，并在下丘脑、中隔、眶额皮质、杏仁核和海马积聚，但未在其他区域积聚。对一只成年母猴进行了对婴儿或性行为的兴趣测试，在每次测试之前接受不同的静脉治疗（1或3mg /kg的L368,899或生理盐水）。OT拮抗剂治疗降低或消除了对婴儿和性行为的兴趣。这些结果虽然是初步的，但却是第一个直接暗示内源性OT在灵长类动物母性兴趣和性行为激活中的作用。虽然外周给药L368,899阻断中枢OT受体仍有待经验证明，但我们的行为研究结果表明，这种非肽拮抗剂可能有助于测试灵长类动物的各种社交和其他行为中OT的参与。(C) 2007爱思唯尔公司版权所有。
Central administration of oxytocin (OT) antagonists inhibits maternal and sexual behavior in non-primates, providing the strongest experimental evidence that endogenous OT facilitates these behaviors. While there have been a few reports that ICV administration of OT increases social behaviors in monkeys, no studies to date have assessed the effects of OT antagonists. Therefore, we studied in rhesus monkeys whether L368,899(R), a non-peptide antagonist produced by Merck that selectively blocks the human uterine OT receptor, penetrates the CNS after peripheral administration and alters female maternal and sexual behavior. In two studies in four male monkeys, L368,899 was injected iv (1 mg/kg) after which (1) CSF samples were collected at intervals over 4 h and (2) brains were collected at 60 min. Assay of samples confirmed that iv-administered L368,899 entered CSF and accumulated in the hypothalamus, septum, orbitofrontal cortex, amygdala and hippocampus, but not other areas. An adult female monkey was tested for interest in either an infant or sexual behavior, receiving a different iv treatment prior to each test (I or 3 mg/kg of L368,899 or saline). OT antagonist treatment reduced or eliminated interest in the infant and sexual behavior. These results, although preliminary, are the first to directly implicate endogenous OT in activation of primate maternal interest and sexual behavior. While it remains to be empirically demonstrated that peripherally administered L368,899 blocks central OT receptors, our behavioral findings suggest that this non-peptide antagonist may facilitate testing OT involvement in a variety of social and other behaviors in primates. (C) 2007 Elsevier Inc. All rights reserved.