Reimets Riin, Raud Sirli, Loomets Maarja, Visnapuu Tanel, Volke Vallo, Reimets Ain, Plaas Mario, Vasar Eero
Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
Behav Brain Res. 2016 Jul 15;308:53-63. doi: 10.1016/j.bbr.2016.04.011. Epub 2016 Apr 11.
There is significant comorbidity between mood disorders and diabetes. Wolfram syndrome-related to deficient WFS1 gene function-causes diabetes and mood disorders in humans. Mice lacking the Wfs1 gene display impaired emotional behaviour and glucose metabolism. Various antidepressant drugs are used for alleviating the symptoms of mood disorders. For this study the tail suspension test and locomotor activity test were used to compare the effects of different antidepressants upon homozygous Wfs1-deficient, heterozygous Wfs1-deficient and wild-type mice. Mouse glucose metabolism was concurrently studied using the glucose tolerance test. We showed that ketamine(10mg/kg),NMDA antagonist, escitalopram(2.5-10mg/kg), selective serotonin reuptake inhibitor(SSRI), and amitriptyline(10mg/kg), noradrenaline and serotonin reuptake inhibitor, elicited a stronger antidepressant-like effect in homozygous Wfs1-deficient mice compared to wild-type mice. The effect of noradrenaline and serotonin reuptake inhibitor desipramine(10 and 20mg/kg) did not differ between genotypes. The dopamine and noradrenaline reuptake inhibitor bupropion(5-20mg/kg) had no significant antidepressant-like effect upon any genotype. Amitriptyline and desipramine potentiated a glucose elevation, escitalopram and bupropion did not affect glucose concentrations, and ketamine improved impaired glucose metabolism in homozygous Wfs1-deficient mice. Therefore, the results of this study suggest that SSRIs are the drugs of choice for the treatment of depressive symptoms in diabetic patients. The efficacy of ketamine for these patients remains to be established. Nonetheless, employing the mechanism of action of ketamine that affected glucose metabolism positively, could be an approach for development of improved antidepressants. Wfs1-deficient mice are likely the good animal model to develop new antidepressants more suitable for depressed patients with diabetes.
情绪障碍与糖尿病之间存在显著的共病现象。与WFS1基因功能缺陷相关的沃尔弗拉姆综合征会导致人类患糖尿病和情绪障碍。缺乏Wfs1基因的小鼠表现出情绪行为和葡萄糖代谢受损。各种抗抑郁药物被用于缓解情绪障碍的症状。在本研究中，采用悬尾试验和自发活动试验来比较不同抗抑郁药对纯合Wfs1基因缺陷型、杂合Wfs1基因缺陷型和野生型小鼠的影响。同时使用葡萄糖耐量试验研究小鼠的葡萄糖代谢。我们发现，NMDA拮抗剂氯胺酮（10mg/kg）、选择性5-羟色胺再摄取抑制剂（SSRI）艾司西酞普兰（2.5 - 10mg/kg）以及去甲肾上腺素和5-羟色胺再摄取抑制剂阿米替林（10mg/kg），与野生型小鼠相比，在纯合Wfs1基因缺陷型小鼠中引发了更强的抗抑郁样效应。去甲肾上腺素和5-羟色胺再摄取抑制剂地昔帕明（10和20mg/kg）的效应在不同基因型之间没有差异。多巴胺和去甲肾上腺素再摄取抑制剂安非他酮（5 - 20mg/kg）对任何基因型都没有显著的抗抑郁样效应。阿米替林和地昔帕明会使血糖升高，艾司西酞普兰和安非他酮不影响血糖浓度，氯胺酮改善了纯合Wfs1基因缺陷型小鼠受损的葡萄糖代谢。因此，本研究结果表明，SSRI类药物是治疗糖尿病患者抑郁症状的首选药物。氯胺酮对这些患者的疗效仍有待确定。尽管如此，利用氯胺酮对葡萄糖代谢产生积极影响的作用机制，可能是开发改进型抗抑郁药的一种途径。Wfs1基因缺陷型小鼠可能是开发更适合糖尿病抑郁症患者的新型抗抑郁药的良好动物模型。
