Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling.
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.
Masood
Anbrin
A
Departments of Behavioral Medicine and Psychiatry and Neurobiology and Anatomy, West Virginia University Health Sciences Center, Morgantown, West Virginia 26506, USA.
Huang
Ying
Y
Hajjhussein
Hassan
H
Xiao
Lan
L
Li
Hao
H
Wang
Wei
W
Hamza
Adel
A
Zhan
Chang-Guo
CG
O'Donnell
James M
JM
D000818:Animals; D014151:Anti-Anxiety Agents; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005092:Exonucleases / Q000037:antagonists & inhibitors*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D014151:Anti-Anxiety Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; D011994:Recombinant Proteins; D014227:Triazines; D000242:Cyclic AMP; D005092:Exonucleases; C022650:spleen exonuclease; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester
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