D-578, an orally active triple monoamine reuptake inhibitor, displays antidepressant and anti-PTSD like effects in rats.
D-578, an orally active triple monoamine reuptake inhibitor, displays antidepressant and anti-PTSD like effects in rats.
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DOI：
10.1016/j.ejphar.2019.172632
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发表时间：
2019-11-05
影响因子：
5
通讯作者：
Perrine, Shane A.
中科院分区：
文献类型：
--
作者：
Dutta, Aloke K.;Santra, Soumava;Harutyunyan, Arman;Das, Banibrata;Lisieski, Michael J.;Xu, Liping;Antonio, Tamara;Reith, Maarten E. A.;Perrine, Shane A.
关键词：
由于目前的药物不足，开发更好的治疗重度抑郁症（MDD）和创伤后应激障碍（PTSD）的药物存在重大未满足的需求。本研究的目的是研究一种新型三重再摄取抑制剂（TRI）D-578的行为药理学特征，该抑制剂对所有三种单胺转运蛋白均表现出纳摩尔效力（Ki; 16.2）。16.2、3.23 nM和29.6、20.6、6.10 nM），对其他脱靶CNS受体几乎没有亲和力。在大鼠强迫游泳试验中，化合物D-578在口服给药后显示出高功效并且不刺激运动行为。D-578和帕罗西汀的作用接下来在创伤应激暴露的大鼠模型--单一延长应激（SPS）模型--中进行评估，该模型已被证明在PTSD的建模方面具有结构、预测和行为有效性。我们的研究结果表明，与假治疗相比，SPS对条件性恐惧的获得没有影响，但损害了恐惧行为的消退学习和消退保持。D-578，而不是帕罗西汀，衰减由SPS引起的消退和注意力保留缺陷。这些发现表明，与帕罗西汀相比，D-578在PTSD模型中使创伤应激诱导的消退-保留学习正常化方面具有更大的功效。总的来说，这些结果表明，D-578，除了产生一个强大的和有效的抗抑郁作用，可能会减弱恐惧记忆的适应不良保留，并支持进一步测试这种药物的抑郁症和创伤后应激障碍的药物治疗。
Significant unmet needs exist for development of better pharmacotherapeutic agents for major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) as the current drugs are inadequate. Our goal in this study is to investigate behavioral pharmacological characterization of a novel triple reuptake inhibitor (TRI) D-578 which exhibits nanomolar potency at all three monoamine transporters (Ki; 16.2. 16.2, 3.23 nM, and 29.6, 20.6, 6.10 nM for the rat brain and cloned human dopamine, serotonin and norepinephrine transporters, respectively) and exhibited little to no affinity for other off-target CNS receptors. In a rat forced swim test, compound D-578 upon oral administration displayed high efficacy and not stimulating in locomotor behavior. The effects of D-578 and paroxetine were next evaluated in a rat model for traumatic stress exposure - the single prolonged stress (SPS) model - which has been shown to have construct, predictive, and behavioral validity in modeling aspects of PTSD. Our results show that SPS had no effect on the acquisition of conditioned fear, but impaired extinction learning and extinction retention of fear behavior compared to sham treatment. D-578, but not paroxetine, attenuated the extinction and extinction-retention deficit induced by SPS. These findings suggest that D-578 has greater efficacy in normalizing traumatic stress-induced extinction-retention learning in a model for PTSD compared to paroxetine. Overall these results suggest that D-578, in addition to producing a robust and efficacious antidepressant effect, may attenuate maladaptive retention of fearful memories and support further testing of this agent for the pharmacotherapy of depression and PTSD.
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影响因子：
--
作者：
KESSLER, RC;SONNEGA, A;NELSON, CB
通讯作者：
NELSON, CB
影响因子：
3.7
作者：
Dutta, Aloke K.;Santra, Soumava;Reith, Maarten E. A.
通讯作者：
Reith, Maarten E. A.
DOI：
10.1073/pnas.91.26.12584
发表时间：
1994-12-20
影响因子：
11.1
作者：
BUCK, KJ;AMARA, SG
通讯作者：
AMARA, SG
影响因子：
--
作者：
Kessler, RC;Berglund, P;Walters, EE
通讯作者：
Walters, EE
影响因子：
5
作者：
Dutta, Aloke K.;Ghosh, Balaram;Reith, Maarten E. A.
通讯作者：
Reith, Maarten E. A.