Masood Anbrin, Huang Ying, Hajjhussein Hassan, Xiao Lan, Li Hao, Wang Wei, Hamza Adel, Zhan Chang-Guo, O'Donnell James M
Departments of Behavioral Medicine and Psychiatry and Neurobiology and Anatomy, West Virginia University Health Sciences Center, Morgantown, West Virginia 26506, USA.
J Pharmacol Exp Ther. 2009 Nov;331(2):690-9. doi: 10.1124/jpet.109.156729. Epub 2009 Aug 14.
Phosphodiesterase (PDE)-2 is a component of the nitric-oxide synthase (NOS)/guanylyl cyclase signaling pathway in the brain. Given recent evidence that pharmacologically induced changes in NO-cGMP signaling can affect anxiety-related behaviors, the effects of the PDE2 inhibitors (2-(3,4-dimethoxybenzyl)-7-det-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one) (Bay 60-7550) and 3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzamide (ND7001), as well as modulators of NO, were assessed on cGMP signaling in neurons and on the behavior of mice in the elevated plus-maze, hole-board, and open-field tests, well established procedures for the evaluation of anxiolytics. Bay 60-7550 (1 microM) and ND7001 (10 microM) increased basal and N-methyl-d-aspartate- or detanonoate-stimulated cGMP in primary cultures of rat cerebral cortical neurons; Bay 60-7550, but not ND7001, also increased cAMP. Increased cGMP signaling, either by administration of the PDE2 inhibitors Bay 60-7550 (0.5, 1, and 3 mg/kg) or ND7001 (1 mg/kg), or the NO donor detanonoate (0.5 mg/kg), antagonized the anxiogenic effects of restraint stress on behavior in the three tests. These drugs also produced anxiolytic effects on behavior in nonstressed mice in the elevated plus-maze and hole-board tests; these effects were antagonized by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (20 mg/kg). By contrast, the NOS inhibitor N(omega)-nitro-l-arginine methyl ester (50 mg/kg), which reduces cGMP signaling, produced anxiogenic effects similar to restraint stress. Overall, the present behavioral and neurochemical data suggest that PDE2 may be a novel pharmacological target for the development of drugs for the treatment of anxiety disorders.
磷酸二酯酶（PDE）-2是大脑中一氧化氮合酶（NOS）/鸟苷酸环化酶信号通路的一个组成部分。鉴于最近有证据表明，药理学诱导的NO-cGMP信号变化可影响焦虑相关行为，本研究评估了PDE2抑制剂（2-(3,4-二甲氧基苄基)-7-脱-5-甲基咪唑-[5,1-f][1,2,4]三嗪-4(3H)-酮）（Bay 60-7550）和3-(8-甲氧基-1-甲基-2-氧代-7-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂卓-5-基)苯甲酰胺（ND7001）以及NO调节剂对神经元中cGMP信号的影响，以及对小鼠在高架十字迷宫、洞板试验和旷场试验中的行为的影响，这些都是评估抗焦虑药物的成熟方法。Bay 60-7550（1 microM）和ND7001（10 microM）增加了大鼠大脑皮质神经元原代培养物中的基础cGMP以及N-甲基-D-天冬氨酸或脱氮诺酸刺激的cGMP；Bay 60-7550增加了cAMP，而ND7001没有。通过给予PDE2抑制剂Bay 60-7550（0.5、1和3 mg/kg）或ND7001（1 mg/kg），或NO供体脱氮诺酸（0.5 mg/kg）来增加cGMP信号，可拮抗束缚应激对这三项试验中行为的致焦虑作用。这些药物在高架十字迷宫和洞板试验中对非应激小鼠的行为也产生了抗焦虑作用；这些作用被鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（20 mg/kg）拮抗。相比之下，降低cGMP信号的NOS抑制剂N(ω)-硝基-L-精氨酸甲酯（50 mg/kg）产生了与束缚应激类似的致焦虑作用。总体而言，目前的行为和神经化学数据表明，PDE2可能是开发治疗焦虑症药物的一个新的药理学靶点。
