Anxiolytic Effects of Phosphodiesterase-2 Inhibitors Associated with Increased cGMP Signaling

• DOI: 10.1124/jpet.109.156729
• Publication Date: 2009-08-15T01:54:41Z
• Authors: Anbrin Masood; Ying Huang; Hassan Hajjhussein; Lan Xiao; Hao Li; Wei Wang; Adel Hamza; Chang-Guo Zhan; James M. O’Donnell
• Keywords: Anxiogenic; Soluble guanylyl cyclase

Phosphodiesterase (PDE)-2 is a component of the nitric-oxide synthase (NOS)/guanylyl cyclase signaling pathway in brain. Given recent evidence that pharmacologically induced changes NO-cGMP can affect anxiety-related behaviors, effects PDE2 inhibitors (2-(3,4-dimethoxybenzyl)-7-det-5-methylimidazo-[5,1-<i>f</i>][1,2,4]triazin-4(3<i>H</i>)-one) (Bay 60-7550) and 3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1<i>H</i>-benzo[<i>e</i>][1,4]diazepin-5-yl)benzamide (ND7001), as well modulators NO, were assessed on cGMP neurons behavior mice elevated plus-maze, hole-board, open-field tests, established procedures for evaluation anxiolytics. Bay 60-7550 (1 μM) ND7001 (10 increased basal <i>N</i>-methyl-d-aspartate- or detanonoate-stimulated primary cultures rat cerebral cortical neurons; 60-7550, but not ND7001, also cAMP. Increased signaling, either by administration (0.5, 1, 3 mg/kg) mg/kg), NO donor detanonoate (0.5 antagonized anxiogenic restraint stress three tests. These drugs produced anxiolytic nonstressed plus-maze hole-board tests; these guanylyl inhibitor 1<i>H</i>-[1,2,4]oxadiazolo[4,3-<i>a</i>]quinoxalin-1-one (20 mg/kg). By contrast, NOS <i>N</i>^ω-nitro-l-arginine methyl ester (50 which reduces similar to stress. Overall, present behavioral neurochemical data suggest may be novel pharmacological target development treatment anxiety disorders.