The novel atypical dopamine transport inhibitor CT-005404 has pro-motivational effects in neurochemical and inflammatory models of effort-based dysfunctions related to psychopathology
The novel atypical dopamine transport inhibitor CT-005404 has pro-motivational effects in neurochemical and inflammatory models of effort-based dysfunctions related to psychopathology
复制标题
DOI：
10.1016/j.neuropharm.2020.108325
复制
发表时间：
2021-02-01
影响因子：
4.7
通讯作者：
Salamone, John D.
中科院分区：
文献类型：
--
作者：
Rotolo, Renee A.;Presby, Rose E.;Salamone, John D.
抑郁症患者患有与努力相关的动机症状，如乏力和疲劳，这些症状对许多常见的抗抑郁药有抗药性。据报道，阻断多巴胺转运（DAT）的药物有积极的激励作用，而DAT抑制剂如可卡因和安非他明会产生不良的副作用。因此，有必要开发和表征具有独特和选择性结合谱的新型非典型DAT抑制剂。啮齿动物基于努力的选择任务为动机功能障碍提供了有用的模型。在这些任务中，动物会在高强度的工具性行动和低强度/低奖励的选择之间做出选择。目前的研究集中在一种新型非典型DAT抑制剂CT-005404的初步表征上，它与DAT结合，相对于5 -羟色胺和去甲肾上腺素的运输具有高选择性，并产生细胞外DA的长期升高。采用固定比例5/chow饲喂选择试验，评估CT-005404减轻DA消耗剂tetrabenazine和促炎细胞因子IL-1 β (IL-1 β)的努力相关激励效应的能力。四苯那嗪（1.0 mg/kg i.p）改变了选择行为，减少了杠杆按压，增加了食物摄入量。IL-1 β (4.0 μ g/kg i.p.)也降低了杠杆按压。将CT-005404与四苯那嗪或IL-1 β (7.5-30.0 mg/kg p.o)共同给药，15.0和30.0 mg/kg剂量显著逆转了四苯那嗪和IL-1 β的作用。单独给药的CT-005404在大鼠的渐进比例/食物喂养选择任务中产生了剂量相关的杠杆按压增加。非典型DAT抑制剂，如CT-005404，为人类动机功能障碍的药物治疗提供了新的途径。
Depressed individuals suffer from effort-related motivational symptoms such as anergia and fatigue, which are resistant to treatment with many common antidepressants. While drugs that block dopamine transport (DAT) reportedly have positive motivational effects, DAT inhibitors such as cocaine and amphetamines produce undesirable side effects. Thus, there is a need to develop and characterize novel atypical DAT inhibitors with unique and selective binding profiles. Rodent effort-based choice tasks provide useful models of motivational dysfunctions. With these tasks, animals choose between a high-effort instrumental action leading to highly valued reinforcement vs. a low effort/low reward option. The present studies focused on the initial characterization of a novel atypical DAT inhibitor, CT-005404, which binds to DAT with high selectivity relative to serotonin and norepinephrine transport, and produces long-term elevations of extracellular DA. CT-005404 was assessed for its ability to attenuate the effort-related motivational effects of the DA depleting agent tetrabenazine and the pro inflammatory cytokine interleukin-1 beta (IL-1 beta) using a fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg i.p.) shifted choice behavior, decreasing lever pressing and increasing chow intake. IL-1 beta (4.0 mu g/kg i.p.) also decreased lever pressing. CT-005404 was co-administered (7.5-30.0 mg/kg p.o.) with either tetrabenazine or IL-1 beta, and the 15.0 and 30.0 mg/kg doses significantly reversed the effects of tetrabenazine and IL-1 beta. CT-005404 administered alone produced a dose-related increase in lever pressing in rats tested on a progressive ratio/chow feeding choice task. Atypical DAT inhibitors such as CT-005404 offer potential as a new avenue for drug treatment of motivational dysfunctions in humans.