Salomé N, Stemmelin J, Cohen C, Griebel G
Sanofi-Aventis, Department of Psychopharmacology, 31 avenue Paul Vaillant-Couturier, Bagneux 92220, France.
Psychopharmacology (Berl). 2006 Aug;187(2):237-44. doi: 10.1007/s00213-006-0424-1. Epub 2006 Jun 2.
SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide), the first selective nonpeptide vasopressin V1b receptor antagonist has been shown to induce antidepressant-and anxiolytic-like effects following systemic administration, whereas intraseptal infusion of the drug engender antidepressant-but not anxiolytic-like effects.
Based on recent evidence that V1b receptors are located within the amygdaloid complex, a structure which is well known for its modulatory role of emotional processes, the possible involvement of the different amygdaloid nuclei in the anxiolytic- and/or antidepressant-like effects of SSR149415 was examined.
Male Sprague-Dawley or Wistar rats were infused with SSR149415 into the central (CeA), the basolateral (BlA), or the medial (MeA) nucleus of the amygdala and tested 10 min after microinjection in the elevated plus-maze or the forced-swimming test, two models typically used for assessing the anxiolytic and antidepressant effects of drugs, respectively.
Microinjection of SSR149415 into the BlA (1-10 ng), but not into the CeA or the MeA, increased the percentage of time spent in the open arms of the elevated plus-maze, indicating anxiolytic-like effects. Furthermore, in the forced-swimming test, microinjection of the drug into the CeA (1, 10, and 100 ng), BlA (1-10 ng), or MeA (100 ng) decreased immobility, an effect which is indicative of an antidepressant-like action. Together, these findings indicate that while the antidepressant-like effects of SSR149415 are mediated by different amygdaloid nuclei, its anxiolytic-like effects appear to involve only the basolateral nucleus of the amygdala. Moreover, these results add further evidence to the role of extrahypothalamic vasopressinergic systems in the control of emotional responses.
SSR149415（(2S, 4R)-1-[5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-2-吡咯烷甲酰胺），首个选择性非肽类血管加压素V1b受体拮抗剂，已被证明全身给药后可诱导出抗抑郁和抗焦虑样效应，而药物的隔内注射则产生抗抑郁但无抗焦虑样效应。
基于近期证据表明V1b受体位于杏仁核复合体中，该结构因其对情绪过程的调节作用而闻名，研究了不同杏仁核在SSR149415抗焦虑和/或抗抑郁样效应中的可能作用。
将雄性Sprague-Dawley或Wistar大鼠杏仁核的中央核（CeA）、基底外侧核（BlA）或内侧核（MeA）注入SSR149415，并于微量注射后10分钟在高架十字迷宫或强迫游泳试验中进行测试，这两种模型通常分别用于评估药物的抗焦虑和抗抑郁作用。
将SSR149415微量注射到BlA（1 - 10纳克），而非CeA或MeA，可增加大鼠在高架十字迷宫开放臂停留时间的百分比，表明具有抗焦虑样效应。此外，在强迫游泳试验中，将药物微量注射到CeA（1、10和100纳克）、BlA（1 - 10纳克）或MeA（100纳克）可减少不动时间，这一效应表明具有抗抑郁样作用。总之，这些发现表明，虽然SSR149415的抗抑郁样效应由不同的杏仁核介导，但其抗焦虑样效应似乎仅涉及杏仁核的基底外侧核。此外，这些结果进一步证明了下丘脑外血管加压素能系统在控制情绪反应中的作用。
