Westrich Ligia, Haddjeri Nasser, Dkhissi-Benyahya Ouria, Sánchez Connie
Lundbeck Research USA, 215 College Avenue, Paramus, NJ 07652, USA.
Neuropharmacology. 2015 Feb;89:382-90. doi: 10.1016/j.neuropharm.2014.10.015.
Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5-HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 μM vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents.
由于昼夜节律同步性差和认知功能障碍与情感障碍有关，因此，针对参与昼夜节律和认知调节的关键5-羟色胺（5-HT，血清素）受体亚型的抗抑郁药可能具有治疗作用。伏硫西汀是一种多模式抗抑郁药，可抑制5-HT1D、5-HT3、5-HT7受体活性以及5-HT再摄取，并增强5-HT1A和5-HT1B受体的活性。在本研究中，我们分别使用基因改造的PER2::LUC小鼠的组织外植体、运动活动节律监测和物体识别测试，研究了伏硫西汀对PER2::LUC表达的周期时长、昼夜节律行为和情景记忆的影响。用0.1μM伏硫西汀孵育PER2::LUC小鼠视交叉上核的组织外植体，可增加PER2生物发光的周期时长。在活动开始前，监测单独或与5-HT1A受体激动剂氟司洛生（2.5mg/kg，皮下注射）或5-HT7受体拮抗剂SB269970（30mg/kg，皮下注射）联合使用伏硫西汀（10mg/kg，皮下注射）处理的Sprague-Dawley大鼠的每日转轮活动，结果显示转轮行为出现显著延迟。在存在5-HT7受体部分激动剂AS19的情况下，伏硫西汀引起的昼夜周期时长增加和相位延迟被消除。最后，在物体识别测试中，伏硫西汀（10mg/kg，腹腔注射）增加了在记忆测试期间探索新物体所花费的时间，而AS19（5mg/kg，腹腔注射）可阻止这种效应。总之，本研究表明，伏硫西汀部分通过其对5-HT7受体的拮抗作用，对昼夜节律产生显著影响，并在啮齿动物中表现出促记忆特性。
