title: Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice.
abstract: OBJECTIVE
  Cyclic nucleotide phosphodiesterase-2 (PDE2) is a potential therapeutic target for the treatment of cognitive dysfunction. Using the object recognition test (ORT), this study assessed the effects of two PDE2 inhibitors, Bay 60-7550 and ND7001, on learning and memory, and examined underlying mechanisms.
  
  
  METHODS
  To assess the role of PDE2 inhibition on phases of memory, Bay 60-7550 (3 mg/kg) was administered: 30 min prior to training; 0, 1, or 3 h after training; or 30 min prior to recall testing. To assess cyclic nucleotide involvement in PDE2 inhibitor-enhanced memory consolidation, either the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg; intraperitoneal (IP)), soluble guanylyl cyclase inhibitor 1H-[-1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 20 mg/kg; IP), protein kinase G inhibitor KT5823 (2.5 μg; intracerebroventricular (ICV)), or protein kinase A inhibitor H89 (1 μg; ICV) was administered 30 min prior to the PDE2 inhibitor Bay 60-7550 (3 mg/kg) or ND7001 (3 mg/kg). Changes in the phosphorylation of 3'5'-cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) at Ser-133 and vasodilator-stimulated phosphoprotein (VASP) at Ser-239 were determined to confirm activation of cAMP and 3'5'-cyclic guanosine monophosphate (cGMP) signaling.
  
  
  RESULTS
  Bay 60-7550 (3 mg/kg) enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg) on early consolidation processes. Bay 60-7550 (3 mg/kg) enhanced phosphorylation of CREB and VASP, both targets of cGMP-dependent protein kinase (PKG).
  
  
  CONCLUSIONS
  These results confirm a potential of PDE2, or components of its signaling pathway, as a therapeutic target for drug discovery focused on restoring memory function.
authors.affiliation: Neuroscience Graduate Program, West Virginia University Health Sciences Center, Morgantown, WV, USA. lmlueptow@mix.wvu.edu.|West Virginia University, 1 Medical Center Drive, PO Box 9128, Morgantown, WV, USA. lmlueptow@mix.wvu.edu.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Lueptow
authors.affiliation: Molecular Modeling and Biopharmaceutical Center and Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY, USA.
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects*; D008813:Mice, Inbred ICR; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D021641:Recognition, Psychology / Q000187:drug effects*; D014227:Triazines / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: 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; D002227:Carbazoles; D015815:Cell Adhesion Molecules; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007093:Imidazoles; D008840:Microfilament Proteins; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D014227:Triazines; D000098662:Vasodilator-Stimulated Phosphoprotein; C073601:KT 5823; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester
keywords: Cognition; Cyclic AMP; Cyclic GMP; Learning and memory; Nitric oxide synthase; Object recognition test; Phosphodiesterase inhibitors; Phosphodiesterase-2; Protein kinase G; Soluble guanylyl cyclase