Griebel Guy, Simiand Jacques, Stemmelin Jeanne, Gal Claudine Serradeil-Le, Steinberg Régis
Sanofi-Synthelabo Recherche, Bagneux, France.
Curr Drug Targets CNS Neurol Disord. 2003 Jun;2(3):191-200. doi: 10.2174/1568007033482850.
The complexity of the stress response would appear to provide multiple opportunities for intervention, but treatment strategies are often centered on the improvement of symptoms rather than attempting to "treat" the stress response. However, recent efforts have begun to focus on the development of pharmacological agents that can attenuate the stress response itself, rather than the symptoms associated with stress. Although CRF, which is the main regulator of the stress system, is the focus of current interest, there is an accumulating body of evidence suggesting that the vasopressinergic system may play an equal role in the regulation of the stress response, and that V(1b) receptor antagonists may be of potential therapeutic benefit. The availability of SSR149415, the first selective antagonist for the V(1b) receptor has allowed us to evaluate this hypothesis. SSR149415 is able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. The latter were active in a wide range of anxiety models, whereas the V(1b) receptor antagonist showed clear-cut effects only in particularly stressful situations. It is important to note that SSR149415 is devoid of central depressant effects, even at high doses, and does not affect cognitive processes, suggesting a large therapeutic window. Altogether, these findings suggest that V(1b) receptor antagonists might be useful as a treatment for major depression and stress disorders that result from traumatic events.
应激反应的复杂性似乎提供了多种干预机会，但治疗策略往往集中在症状的改善上，而不是试图“治疗”应激反应本身。然而，最近的研究开始关注开发能够减弱应激反应本身而非与应激相关症状的药物。虽然作为应激系统主要调节因子的促肾上腺皮质激素释放因子（CRF）是当前研究的焦点，但越来越多的证据表明，血管加压素能系统在应激反应的调节中可能发挥同等作用，并且血管加压素1b（V1b）受体拮抗剂可能具有潜在的治疗益处。首个V1b受体选择性拮抗剂SSR149415的出现使我们能够评估这一假设。SSR149415能够减弱啮齿动物中一些但并非所有与应激相关的行为。虽然该化合物的抗抑郁样活性与参考抗抑郁药相当，但其在焦虑测试中显示的总体特征与经典抗焦虑药（如苯二氮䓬类药物）不同。后者在广泛的焦虑模型中都有活性，而V1b受体拮抗剂仅在特别应激的情况下显示出明确的效果。值得注意的是，即使在高剂量下，SSR149415也没有中枢抑制作用，并且不影响认知过程，这表明其具有较大的治疗窗口。总之，这些发现表明V1b受体拮抗剂可能作为治疗重大抑郁症和由创伤性事件导致的应激障碍的药物。
