Hufgard Jillian R, Williams Michael T, Skelton Matthew R, Grubisha Olivera, Ferreira Filipa M, Sanger Helen, Wright Mary E, Reed-Kessler Tracy M, Rasmussen Kurt, Duman Ronald S, Vorhees Charles V
Division of Neurology (MLC 7044), Department of Pediatrics, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Ave., Cincinnati, OH, USA.
Neuroscience Research Division, Lilly Research Centre, Eli Lilly & Co. Ltd., Windlesham, Surrey, UK.
Psychopharmacology (Berl). 2017 Jun;234(12):1803-1813. doi: 10.1007/s00213-017-4587-8. Epub 2017 Mar 23.
Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets.
We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress.
Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined.
Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress.
PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.
重度抑郁症是自杀和致残的主要原因。尽管如此，目前的抗抑郁药在超过60%的患者中疗效不足。当前大多数抗抑郁药是突触前再摄取抑制剂；突触后信号调节作为潜在治疗靶点尚未受到同等程度的关注。
我们研究了破坏突触后环核苷酸水解酶磷酸二酯酶（PDE）1b对抑郁样行为的影响，以及应激后对野生型（WT）小鼠PDE1B蛋白的影响。
对同窝基因敲除（KO）小鼠和WT小鼠进行运动活动、悬尾试验（TST）和强迫游泳试验（FST）。FST还用于比较两种抗抑郁药氟西汀和安非他酮对KO小鼠与WT小鼠的影响。还测定了信使核糖核酸（mRNA）表达变化。对WT小鼠进行急性或慢性应激，并检测应激标志物和PDE1B表达。
Pde1b基因敲除小鼠在TST和FST中的不动时间减少。用抗抑郁药治疗时，WT小鼠和KO小鼠在FST中的不动时间均减少，且在KO小鼠中这种作用具有叠加性。缺乏Pde1b的小鼠纹状体中Pde10a mRNA表达增加。在WT小鼠中，急性和慢性应激上调PDE1B表达，而慢性应激后而非急性应激后PDE10A表达下调。
由于在Pde1b基因敲除小鼠中观察到抗抑郁样表型，PDE1B是抑郁症治疗的潜在治疗靶点。
