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首页> 外文期刊>Journal of neuroendocrinology >The Nonpeptide Oxytocin Receptor Agonist WAY 267,464: Receptor-Binding Profile, Prosocial Effects and Distribution of c-Fos Expression in Adolescent Rats
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The Nonpeptide Oxytocin Receptor Agonist WAY 267,464: Receptor-Binding Profile, Prosocial Effects and Distribution of c-Fos Expression in Adolescent Rats

机译：非肽催产素受体激动剂WAY 267,464：青春期大鼠的受体结合特征，亲社会效应和c-Fos表达分布

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Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V 1aR) pharmacology and regional patterns of c-Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus-maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100mg/kg, i.p.) or oxytocin (0.1 and 1mg/kg, i.p.). The higher doses were also examined for their effects on regional c-Fos expression. Results showed that WAY 267,464 had higher affinity (K i) at the V 1aR than the OTR (113 versus 978nm). However, it had no functional response at the V 1aR and only a weak functional effect (EC 50) at the OTR (881nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V 1aR antagonist. Oxytocin showed high binding at the OTR (1.0nm) and V 1aR (503nm), with a functional EC 50 of 9.0 and 59.7nm, respectively, indicating it is a potent OTR agonist and full V 1aR agonist. WAY 267,464 (100mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c-Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c-Fos expression in the medial amygdala and the supraoptic nucleus than oxytocin, and lesser effects in the locus coeruleus. Overall, our results confirm the differential effects of WAY 267,464 and oxytocin and suggest that this may reflect contrasting actions of WAY 267,464 and oxytocin at the V 1aR. Antagonism of the V 1aR by WAY 267,464 could underlie some of the prosocial effects of this drug either through a direct action or through disinhibition of oxytocin circuitry that is subject to vasopressin inhibitory influences.
机译：先前的研究表明，非肽催产素受体（OTR）激动剂WAY 267,464可能仅部分模拟了催产素在啮齿动物中的作用。本研究进一步探讨了这些差异，并将其与OTR和加压素1a受体（V 1aR）药理学和c-Fos表达的区域模式相关。 WAY 267,464与催产素的结合数据是通过细胞膜上的置换结合测定获得的，而功能受体数据是通过萤光素酶报告基因测定得出的。为了进行行为测试，对青春期大鼠进行了社会偏好范式，高迷宫（EPM）测试以及WAY 267,464（10和100mg / kg，ip）或催产素（0.1和1mg / kg，ip）后运动能力的变化。还检查了较高剂量对区域c-Fos表达的影响。结果显示，WAY 267,464在V 1aR处的亲和力（K i）比OTR高（113对978nm）。但是，它在V 1aR处没有功能响应，而在OTR（881nm）处只有较弱的功能效应（EC 50）。这表明WAY 267,464是一种亲和力较弱的OTR激动剂，可能是V 1aR拮抗剂。催产素在OTR（1.0nm）和V 1aR（503nm）处显示出高结合力，功能性EC 50分别为9.0和59.7nm，表明它是有效的OTR激动剂和完整的V 1aR激动剂。在社会偏好测试中，WAY 267,464（100mg / kg），但不是催产素，显着增加了活鼠与假鼠在一起的时间比例。两种化合物均未影响EPM行为，而较高剂量的WAY 267,464和催产素可抑制运动活性。 WAY 267,464和催产素在室下丘脑旁核，杏仁核中央，臂臂旁核和孤立道核中产生相似的c-Fos表达，表明在OTR上使用不同的剂量具有共同的作用。但是，WAY 267,464引起的杏仁核和视上核的c-Fos表达高于催产素，而对蓝斑的影响较小。总的来说，我们的结果证实了WAY 267,464和催产素的差异作用，并表明这可能反映了WAY 267,464和催产素在V 1aR处的对比作用。通过途径267,464对V 1aR的拮抗作用可能是该药物通过直接作用或通过抑制受加压素抑制作用的催产素回路而产生的亲社会作用。

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