Phosphodiesterases in the Central Nervous System: Implications in Mood and Cognitive Disorders

  • Ying Xu
  • Han-Ting Zhang
  • James M. O’DonnellEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 204)


Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that are involved in the regulation of the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) by controlling their rates of hydrolysis. There are 11 different PDE families and each family typically has multiple isoforms and splice variants. The PDEs differ in their structures, distribution, modes of regulation, and sensitivity to inhibitors. Since PDEs have been shown to play distinct roles in processes of emotion and related learning and memory processes, selective PDE inhibitors, by preventing the breakdown of cAMP and/or cGMP, modulate mood and related cognitive activity. This review discusses the current state and future development in the burgeoning field of PDEs in the central nervous system. It is becoming increasingly clear that PDE inhibitors have therapeutic potential for the treatment of neuropsychiatric disorders involving disturbances of mood, emotion, and cognition.


Anxiety cAMP cGMP Cognition Depression Phosphodiesterases Schizophrenia 


  1. Abel T, Nguyen PV, Barad M, Deuel TAS, Kandel ER (1997) Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus based long term memory. Cell 88:615–626PubMedCrossRefGoogle Scholar
  2. Ahmed T, Frey JU (2005) Phosphodiesterase 4B (PDE4B) and cAMP-level regulation within different tissue fractions of rat hippocampal slices during long-term potentiation in vitro. Brain Res 1041:212–222PubMedCrossRefGoogle Scholar
  3. Aizawa T, Wei H, Miano JM, Abe J, Berk BC, Yan C (2003) Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circ Res 93:406–413PubMedCrossRefGoogle Scholar
  4. Akhondzadeh S (1999) Hippocampal synaptic plasticity and cognition. J Clin Pharm Ther 24:241–248PubMedCrossRefGoogle Scholar
  5. Anjum R, Blenis J (2008) The RSK family of kinases: emerging roles in cellular signaling. Nat Rev Mol Cell Biol 9:747–758PubMedCrossRefGoogle Scholar
  6. Bach ME, Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, Mansuy I, Hawkins RD, Kandel ER (1999) Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci USA 96:5280–5285PubMedCrossRefGoogle Scholar
  7. Baillie GS, MacKenzie SJ, McPhee I, Houslay MD (2000) Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases. Br J Pharmacol 13:811–819CrossRefGoogle Scholar
  8. Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E (1998) Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci USA 95:15020–15025PubMedCrossRefGoogle Scholar
  9. Baratti CM, Boccia MM (1999) Effects of sildenafi l on long-term retention of an inhibitory avoidance response in mice. Behav Pharmacol 10:731–737PubMedCrossRefGoogle Scholar
  10. Barnette MS, Underwood DC (2000) New phosphodiesterase inhibitors as therapeutics for the treatment of chronic lung disease. Curr Opin Pulm Med 6:164–169PubMedCrossRefGoogle Scholar
  11. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520PubMedCrossRefGoogle Scholar
  12. Birnbaum SG, Gobeske KT, Auerbach J, Taylor JR, Arnsten AFT (1999) A role for norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in prefrontal cortex. Biol Psychiatry 46:1266–1274PubMedCrossRefGoogle Scholar
  13. Blokland A, Schreiber R, Prickaerts J (2006) Improving memory: a role for phosphodiesterases. Curr Pharm Des 12:2511–2523PubMedCrossRefGoogle Scholar
  14. Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, de Vente J, Prickaerts J, Blokland A, Koenig G (2004) Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47:1081–1092PubMedCrossRefGoogle Scholar
  15. Bolger G, Michaeli T, Martins T, St John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K (1993) A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol 13:6558–6571PubMedGoogle Scholar
  16. Bolger GB, Rodgers L, Riggs M (1994) Differential CNS expression of alternative mRNA isoforms of the mammalian genes encoding cAMP-specific phosphodiesterases. Gene 149:237–244PubMedCrossRefGoogle Scholar
  17. Bon CL, Garthwaite J (2003) On the role of nitric oxide in hippocampal long-term potentiation. J Neurosci 23:1941–1948PubMedGoogle Scholar
  18. Bos JL (2006) Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 31:680–686PubMedCrossRefGoogle Scholar
  19. Bourtchouladze R, Lidge R, Catapano R, Stanley J, Gossweiler S, Romashko D, Scott R (2003) A mouse model of Rubinstein–Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc Natl Acad Sci USA 100:10518–10522PubMedCrossRefGoogle Scholar
  20. Bouton ME, Westbrook RF, Corcoran KA, Maren S (2006) Contextual and temporal modulation of extinction: behavioral and biological mechanisms. Biol Psychiatry 60:352–360PubMedCrossRefGoogle Scholar
  21. Brink CB, Clapton JD, Eagar BE, Harvey BH (2008) Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies. J Neural Transm 115:117–125PubMedCrossRefGoogle Scholar
  22. Bruel-Jungerman E, Davis S, Rampon C, Laroche S (2006) Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 26:5888–5893PubMedCrossRefGoogle Scholar
  23. Bruel-Jungerman E, Rampon C, Laroche S (2007) Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Rev Neurosci 18:93–114PubMedCrossRefGoogle Scholar
  24. Bunge SA, Ochsner KN, Desmond JE, Glover GH, Gabrieli JD (2001) Prefrontal regions involved in keeping information in and out of mind. Brain 124:2074–2086PubMedCrossRefGoogle Scholar
  25. Cassel JC, Cassel S, Galani R, Kelche C, Will B, Jarrard L (1998) Fimbria-fornix vs. selective hippocampal lesions in rats: effects on locomotor activity and spatial learning and memory. Neurobiol Learn Mem 69:22–45PubMedCrossRefGoogle Scholar
  26. Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, Gilliam TC, Kandel ER (2003) Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39:655–669PubMedCrossRefGoogle Scholar
  27. Chen CC, Yang CH, Huang CC, Hsu KS (2010) Acute stress impairs hippocampal mossy fiber-CA3 long-term potentiation by enhancing cAMP-specific phosphodiesterase 4 activity. Neuropsychopharmacology 35:1605–1617PubMedCrossRefGoogle Scholar
  28. Cheng YF, Wang C, Lin HB, Li YF, Huang Y, Xu JP, Zhang HT (2010) Inhibition of phosphodiesterase-4 reverses memory deficits produced by Abeta 25-35 or Abeta1-40 peptide in rats. Psychopharmacology 212:181–191Google Scholar
  29. Cherry JA, Davis RL (1999) Cyclic AMP phosphodiesterases are location in region of the mouse brain associate with reinforcement, movement, and effect. J Comp Neurol 407:287–301PubMedCrossRefGoogle Scholar
  30. Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54:387–402PubMedCrossRefGoogle Scholar
  31. Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511PubMedCrossRefGoogle Scholar
  32. Conti M, Nemoz G, Sette C, Vicini E (1995) Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr Rev 16:370–389PubMedGoogle Scholar
  33. Conti M, Richter W, Mehats C, Livera G, Park JY, Jin C (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278:5493–5496PubMedCrossRefGoogle Scholar
  34. Coquil JF, Franks DJ, Wells JN, Dupuis M, Hamet P (1980) Characteristics of a new binding protein distinct from the kinase for guanosine 3, 5-monophosphate in rat platelets. Biochim Biophys Acta 631:148–165PubMedGoogle Scholar
  35. Coven E, Ni Y, Widnell KL, Chen J, Walker WH, Habener JF, Nestler EJ (1998) Cell type-specific regulation of CREB gene expression: mutational analysis of CREB promoter activity. J Neurochem 71:1865–1874PubMedCrossRefGoogle Scholar
  36. Crowe SM, Streetman DS (2002) Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 162:1349–1360CrossRefGoogle Scholar
  37. De Vente J, Hopkins DA, Markerink-van Ittersum M, Steinbusch HWM (1996) Effects of the 3′, 5′-phosphodiesterase inhibitors isobutylmethylxanthine and zaprinast on NO-mediated cGMP accumulation in the hippocampus slice preparation: an immunocytochemical study. J Chem Neuroanat 10:241–248PubMedCrossRefGoogle Scholar
  38. DeNoble VJ (1987) Vinpocitine enhances retrieval of a step-through passive avoidance response in rats. Pharmacol Biochem Behav 26:183–186PubMedCrossRefGoogle Scholar
  39. Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL (2009) Amelioration of intracerebroventricular strepozotion induced cognitive dysfunction and oxidate stress by vinpocetine – a PDE1 inhibitor. Eur J Pharmacol 620:49–56PubMedCrossRefGoogle Scholar
  40. Devan BD, Sierra-Mercado D Jr, Jimenez M, Bowker JL, Duffy KB, Spangler EL, Ingram DK (2004) Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats. Pharmacol Biochem Behav 79:691–699PubMedCrossRefGoogle Scholar
  41. Dhir A, Kulkarni SK (2007a) Effect of addition of yohimbine (alpha-2-receptor antagonist) to the antidepressant activity of fluoxetine or venlafaxine in the mouse forced swim test. Pharmacology 80:239–243PubMedCrossRefGoogle Scholar
  42. Dhir A, Kulkarni SK (2007b) Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor. Eur J Pharmacol 568:177–185PubMedCrossRefGoogle Scholar
  43. Dlaboga D, Hajjhussein H, O’Donnell JM (2006) Regulation of phosphodiesterase-4 (PDE4) expression in mouse brain by repeat antidepressant treatment: comparison with rolipram. Brain Res 1096:104–112PubMedCrossRefGoogle Scholar
  44. Domek-Łopacińska KU, Strosznajder JB (2008) The effect of selective inhibition of cyclic GMP hydrolyzing phosphodiesterases 2 and 5 on learning and memory processes and nitric oxide synthase activity in brain during aging. Brain Res 1216:68–77PubMedCrossRefGoogle Scholar
  45. Domek-Łopacińska KU, Strosznajder JB (2010) Cyclic GMP and nitric oxide synthase in aging and Alzheimer's disease. Mol Neurobiol 41:129–137PubMedCrossRefGoogle Scholar
  46. Doyle C, Hölscher C, Rowan MJ, Anwyl R (1996) The selective neuronal NO synthase inhibitor 7-nitroindazole blocks both long-term potentiation and depotentiation of field EPSPs in rat hippocampal CA1 in vivo. J Neurosci 16:418–424PubMedGoogle Scholar
  47. Duman RS (2002) Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry 17:306–310PubMedCrossRefGoogle Scholar
  48. Duman RS, Malberg J, Thome J (1999) Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 46:1181–1191PubMedCrossRefGoogle Scholar
  49. Dumaz N, Marais R (2003) Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. J Biol Chem 278:29819–29823PubMedCrossRefGoogle Scholar
  50. Dunkern TR, Hatzelmann A (2007) Characterization of inhibitors of phosphodiesterase 1C on a human cellular system. FEBS J 274:4812–4824PubMedCrossRefGoogle Scholar
  51. Egan M, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269PubMedCrossRefGoogle Scholar
  52. Einat H, Yuan P, Manji HK (2005) Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. Behav Brain Res 165:172–180PubMedCrossRefGoogle Scholar
  53. Engels P, Abdel’Al S, Hulley P, Lübbert H (1995) Brain distribution of four rat homologues of the Drosophila dunce cAMP phosphodiesterase. J Neurosci Res 41:169–178PubMedCrossRefGoogle Scholar
  54. Epp JR, Spritzer MD, Galea LA (2007) Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation. Neuroscience 149:273–285PubMedCrossRefGoogle Scholar
  55. Esposito K, Reierson GW, Luo HR, Wu GS, Licinio J, Wong ML (2009) Phosphodiesterase genes and antidepressant treatment response: a review. Ann Med 41:177–185PubMedCrossRefGoogle Scholar
  56. Fatemi SH, King DP, Reutiman TJ, Folsom TD, Laurence JA, Lee S, Fan YT, Paciga SA, Conti M, Menniti FS (2008) PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res 101:36–49PubMedCrossRefGoogle Scholar
  57. Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S, Hetman J, Beavo JA, Phillips SC (2000) Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci USA 97:3702–3707PubMedCrossRefGoogle Scholar
  58. Filgueiras CC, Krahe TE, Medina AE (2010) Phosphodiesterase type 1 inhibition improves learning in rats exposed to alcohol during the third trimester equivalent of human gestation. Neurosci Lett 473:202–207PubMedCrossRefGoogle Scholar
  59. Fink HA, Mac Donald R, Rutks IR, Nelson DB, Wilt TJ (2002) Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 162:1349–1360PubMedCrossRefGoogle Scholar
  60. Francis SH (2005) Phosphodiesterase 11 (PDE11): is it a player in human testicular function? Int J Impot Res 17:467–468PubMedCrossRefGoogle Scholar
  61. Francis SH, Lincoln TM, Corbin JD (1980) Characterization of a novel cGMP binding protein from rat lung. J Biol Chem 255:620–626PubMedGoogle Scholar
  62. Francis SH, Busch JL, Corbin JD (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62:525–563PubMedCrossRefGoogle Scholar
  63. Frey U, Huang Y, Kandel ER (1993) Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 260:1661–1664PubMedCrossRefGoogle Scholar
  64. Fujioka T, Fujioka A, Duman RS (2004) Activation of cAMP signaling facilitates themorphological maturation of newborn neurons in adult hippocampus. J Neurosci 24:319–328PubMedCrossRefGoogle Scholar
  65. Fujishige K, Kotera J, Omori K (1999) Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE 10A. Eur J Biochem 266:1118–1127PubMedCrossRefGoogle Scholar
  66. Gao Y, Deng K, Hou J, Bryson JB, Barco A, Nikulina E, Spencer T, Mellado W, Kandel ER, Filbin MT (2004) Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44:609–621PubMedCrossRefGoogle Scholar
  67. Garthwaite J, Boulton CL (1995) Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57:683–706PubMedCrossRefGoogle Scholar
  68. Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O (2004) Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 114:1624–1634PubMedGoogle Scholar
  69. Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE (2006) camp is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11. J Biol Chem 281:2841–2846PubMedCrossRefGoogle Scholar
  70. Guo J, Watson A, Kempson J, Carlsen M, Barbosa J, Stebbins K, Lee D, Dodd J, Nadler SG, McKinnon M, Barrish J, Pitts WJ (2009) Identification of potent pyrimidine inhibitors of phosphodiesterase 7 (PDE7) and their ability to inhibit T cell proliferation. Bioorg Med Chem Lett 19:1935–1938PubMedCrossRefGoogle Scholar
  71. Hajjhussein H, Suvarna NU, Gremillion C, Chandler LJ, O’Donnell JM (2007) Changes in NMDA receptor-induced cyclic nucleotide synthesis regulated the age-dependent increase in PDE4A expression in primary cortical cultures. Brain Res 1149:58–68PubMedCrossRefGoogle Scholar
  72. Haley JE, Malen PL, Chapman PF (1993) Nitric oxide synthase inhibitors block long term potentiation induced by weak but not strong tetanic stimulation at physiological brain temperatures in rat hippocampal slices. Neurosci Lett 160:85–88PubMedCrossRefGoogle Scholar
  73. Han P, Zhu XY, Michaeli T (1997) Alternative splicing of the high affinity cAMP-specific phosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart. J Biol Chem 272:16152–16157PubMedCrossRefGoogle Scholar
  74. Han P, Werber J, Surana M, Fleischer N, Michaeli T (1999) The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. J Biol Chem 274:22337–22344PubMedCrossRefGoogle Scholar
  75. Hartell NA (1996) Inhibition of cGMP breakdown promotes the induction of cerebellar long-term depression. J Neurosci 16:2881–2890PubMedGoogle Scholar
  76. Hebb ALO, Robertson HA, Denovan-Wright EM (2004) Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington’s Disease transgenic mice prior to the onset of motor symptoms. Neuroscience 123:967–981PubMedCrossRefGoogle Scholar
  77. Hebb AL, Robertson HA, Denovan-Wright EM (2008) Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice. Eur Neuropsychopharmacol 18:339–363PubMedCrossRefGoogle Scholar
  78. Heikaus CC, Pandit J, Klevit RE (2009) Cyclic nucleotide binding GAF domains from phosphodiesterases: structural and mechanistic insights. Structure 17:1551–1557PubMedCrossRefGoogle Scholar
  79. Holtmaat AJ, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X, Knott GW, Svoboda K (2005) Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45:279–291PubMedCrossRefGoogle Scholar
  80. Houslay MD (2001) PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol Biol 69:249–315PubMedCrossRefGoogle Scholar
  81. Houslay MD (2010) Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 35:91–100PubMedCrossRefGoogle Scholar
  82. Houslay MD, Schafer P, Zhang KY (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10:1503–1519PubMedCrossRefGoogle Scholar
  83. Houslay MD, Baillie GS, Maurice DH (2007) cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100:950–966PubMedCrossRefGoogle Scholar
  84. Hu H, McCaw EA, Hebb AL, Gomez GT, Denovan-Wright EM (2004) Mutant huntingtin affects the rate of transcription of striatum-specific isoforms of phosphodiesterase 10A. Eur J Neurosci 20:3351–3363PubMedCrossRefGoogle Scholar
  85. Impey S, Mark M, Villacres EC, Poser S, Chavkin C, Storm DR (1996) Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16:973–982PubMedCrossRefGoogle Scholar
  86. Itoh T, Tokumura M, Abe K (2004) Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats. Eur J Pharmacol 498:135–142PubMedCrossRefGoogle Scholar
  87. Juilfs DM, Fulle HJ, Zhao AZ, Houslay MD, Garbers DL, Beavo JA (1997) A subset of olfactory neurons that selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclase-D define a unique olfactory signal transduction pathway. Proc Natl Acad Sci USA 94:3388–3395PubMedCrossRefGoogle Scholar
  88. Kadoshima-Yamaoka K, Murakawa M, Goto M, Tanaka Y, Inoue H, Murafuji H, Nagahira A, Hayashi Y, Nagahira K, Miura K, Nakatsuka T, Chamoto K, Fukuda Y, Nishimura T (2009) ASB16165, a novel inhibitor for phosphodiesterase 7A (PDE7A), suppresses IL-12-induced IFN-gamma production by mouse activated T lymphocytes. Immunol Lett 122:193–197PubMedCrossRefGoogle Scholar
  89. Kaulen P, Brüning G, Schneider HH, Sarter M, Baumgarten HG (1989) Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram. Brain Res 503:229–245PubMedCrossRefGoogle Scholar
  90. Kelly MP, Brandon NJ (2009) Differential function of phosphodiesterase families in the brain: gaining insights through the use of genetically modified animals. Prog Brain Res 179:67–73PubMedCrossRefGoogle Scholar
  91. Kelly MP, Logue SF, Brennan J, Day JP, Lakkaraju S, Jiang L, Zhong X, Tam M, Sukoff Rizzo SJ, Platt BJ, Dwyer JM, Neal S, Pulito VL, Agostino MJ, Grauer SM, Navarra RL, Kelley C, Comery TA, Murrills RJ, Houslay MD, Brandon NJ (2010) Phosphodiesterase 11A in brain is enchriched in ventral hippocampus and deletion cause psychiatric disease related phenotypes. Neuroscience 107:8457–8462Google Scholar
  92. Kleppisch T (2009) Phosphodiesterases in the central nervous system. Handb Exp Pharmacol 191:71–92PubMedCrossRefGoogle Scholar
  93. Kobayashi T, Gamanuma M, Sasaki T, Yamashita Y, Yuasa K, Kotera J, Omori K (2003) Molecular comparison of rat cyclic nucleotide phosphodiesterase 8 family: unique expression of PDE8B in rat brain. Gene 319:21–31PubMedCrossRefGoogle Scholar
  94. Kotaleski JH, Blackwel Kim T (2010) Modelling the molecular mechanisms of synaptic plasticity using systems biology approaches. Neuroscience 11:239–249PubMedGoogle Scholar
  95. Kruuse C, SergeiD R, Tejvir S (2001) The role of cGMP hydrolyzing phosphodiesterase 1 and 5 in cerebral artery dilatation. Eur J Pharmacol 420:55–65PubMedCrossRefGoogle Scholar
  96. Lee R, Wolda S, Moon E, Esselstyn J, Hertel C, Lerner A (2002) PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP. Cell Signal 14:277–284PubMedCrossRefGoogle Scholar
  97. Lehericy S, Gerardin E (2002) Normal functional imaging of the basal ganglia. Epileptic Disord 4:S23–S30PubMedGoogle Scholar
  98. Lepage M, Ghaffar O, Nyberg L, Tulving E (2000) Prefrontal cortex and episodic memory retrieval mode. Proc Natl Acad Sci USA 97:506–511PubMedCrossRefGoogle Scholar
  99. Li L, Yee C, Beavo JA (1999) CD3- and CD28-Dependent Induction of PDE7 Required for T Cell Activation. Science 283:848–851PubMedCrossRefGoogle Scholar
  100. Li YF, Huang Y, Amsdell SL, Xiao L, O’Donnell JM, Zhang HT (2009) Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 (PDE4) inhibitor rolipram on behavior depend on cyclic AMP-response element binding protein (CREB)-mediated neurogenesis in the hippocampus. Neuropsychopharmacology 34:2404–2419PubMedCrossRefGoogle Scholar
  101. Liebenberg N, Harvey BH, Brand L, Brink CB (2010) Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression. Behav Pharmacol 21(5–6):540–547PubMedCrossRefGoogle Scholar
  102. Lin CS (2004) Tissue expression, distribution, and regulation of PDE5. Int J Impot Res 16:8–10CrossRefGoogle Scholar
  103. Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623PubMedCrossRefGoogle Scholar
  104. Loughney K, Snyder PB, Uher L, Rosman GJ, Ferguson K, Florio VA (1999) Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase. Gene 234:109–117PubMedCrossRefGoogle Scholar
  105. Loughney K, Taylor J, Florio VA (2005) Original research 3′, 5′-Cyclic nucleotide phosphodiesterase 11A: localization in human tissues. Int J Impot Res 17:320–325PubMedCrossRefGoogle Scholar
  106. Lu YF, Kandel ER, Hawkins RD (1999) Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci 19:10250–10261PubMedGoogle Scholar
  107. Lucassen H (2004) Pediatric hospice: a second home. Pflege Z 57:854–855PubMedGoogle Scholar
  108. Lugnier C (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109:366–398PubMedCrossRefGoogle Scholar
  109. MacKenzie SJ, Baillie GS, McPhee I, Bolger GB, Houslay MD (2000) ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions. J Biol Chem 275:16609–16617PubMedCrossRefGoogle Scholar
  110. MacKenzie SJ, Baillie GS, McPhee I, MacKenzie C, Seamons R, McSorley T, Millen J, Beard MB, van Heeke G, Houslay MD (2002) Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in upstream conserved region 1 (UCR1). Br J Pharmacol 136:421–433PubMedCrossRefGoogle Scholar
  111. Makhlouf A, Kshirsagar A, Niederberger C (2006) Phosphodiesterase 11: a brief review of structure, expression and function. Int J Impot Res 18:501–509PubMedCrossRefGoogle Scholar
  112. Martinez SE, Beavo JA, Hol WG (2002) GAF domains: two-billion-year-old molecular switches that bind cyclic nucleotides. Mol Interv 2:317–323PubMedCrossRefGoogle Scholar
  113. Masood A, Nadeem A, Mustafa SJ, O’Donnell JM (2008) Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice. J Pharmacol Exp Ther 326:369–379PubMedCrossRefGoogle Scholar
  114. Masood A, Huang Y, Hajjhussein H, Xiao L, Li H, Wang W, Hamza A, Zhan CG, O’Donnell JM (2009) Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling. J Pharmacol Exp Ther 331:690–699PubMedCrossRefGoogle Scholar
  115. Matousovic K, Grande JP, Chini CC, Chini EN, Dousa TP (1995) Inhibitors of cyclic nucleotide phosphodiesterase isozymes type-III and type-IV suppress mitogenesis of rat mesangial cells. J Clin Invest 96:401–410PubMedCrossRefGoogle Scholar
  116. Maurice DH, Haslam RJ (1990) Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP. Mol Pharmacol 37:671–681PubMedGoogle Scholar
  117. McPhee I, Cochran S, Houslay MD (2001) The novel long PDE4A10 cyclic AMP phosphodiesterase shows a pattern of expression within brain that is distinct from the long PDE4A5 and short PDE4A1 isoforms. Cell Signal 13:911–918PubMedCrossRefGoogle Scholar
  118. Mendelovic S, Doron A, Eilat E (1997) Short note: can depressive patients exploit the immune system for suicide. Med Hypotheses 49:445–446CrossRefGoogle Scholar
  119. Mendelovic S, Doron A, Shoenfeld Y (1999) Depression and the immune system. Harefuah 136:88–91Google Scholar
  120. Menniti FS, Faraci WS, Schmidt CJ (2006) Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5:660–670PubMedCrossRefGoogle Scholar
  121. Menniti FS, Chappie TA, Humphrey JM, Schmidt CJ (2007) Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. Curr Opin Investig Drugs 8:54–59PubMedGoogle Scholar
  122. Meyer MR, Angele A, Kremmer E, Kaupp B, Muller F (2000) A cGMP-signaling pathway in subset of olfactory sensory neurons. PNAS 97:10595–10600PubMedCrossRefGoogle Scholar
  123. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR (2005) DISCI and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310:1187–1191PubMedCrossRefGoogle Scholar
  124. Millar JK, Mackie S, Clapcote SJ, Murdoch H, Pickard BS, Christie S, Muir WJ, Blackwood DH, Roder JC, Houslay MD, Porteous DJ (2007) Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness. J Physiol 584:401–405PubMedCrossRefGoogle Scholar
  125. Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V, Rybalkin SD, Beavo JA, Chen YF, Li JD, Blaxall BC, Abe J, Yan C (2009) Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res 105:956–964PubMedCrossRefGoogle Scholar
  126. Miro X, Perez-Torres S, Palacios JM, Puigdomenech P, Mengod G (2001) Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs. Synapse 40:201–204PubMedCrossRefGoogle Scholar
  127. Miró X, Pérez-Torres S, Puigdomènech P, Palacios JM, Mengod G (2002) Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization. Synapse 45:259–269PubMedCrossRefGoogle Scholar
  128. Miyamoto E (2006) Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. J Pharmacol Sci 100:433–442PubMedCrossRefGoogle Scholar
  129. Molnar P, Gaal L (1992) Effect of different subtypes of cognition enhancers on longterm potentiation in the rat dentate gyrus in vitro. Eur J Pharmacol 215:17–22PubMedCrossRefGoogle Scholar
  130. Monfort P, Muñoz MD, Kosenko E, Llansola M, SÃnchez-Pérez A, Cauli O, Felipo V (2004) Sequential activation of soluble guanylate cyclase, protein kinase G and cGMP-degrading phosphodiesterase is necessary for proper induction of long-term potentiation in CA1 of hippocampus. Alterations in hyperammonemia. Neurochem Int. 2004 Nov;45(6):895–901CrossRefGoogle Scholar
  131. Monti B, Berteotti C, Contestabile A (2006) Subchronic Rolipram Delivery Activates Hippocampal CREB and Arc, Enhances Retention and Slows Down Extinction of Conditioned Fear. Neuropsychopharmacology 31:278–286PubMedCrossRefGoogle Scholar
  132. Mori F, Pérez-Torres S, De Caro R, Porzionato A, Macchi V, Beleta J, Gavaldà A, Palacios JM, Mengod G (2010) The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. J Chem Neuroanat 40:36–42PubMedCrossRefGoogle Scholar
  133. Mueller EM, Hofmann SG, Cherry JA (2010) The type IV phosphodiesterase inhibitor rolipram disturbs expression and extinction of conditioned fear in mice. Neuropharmacology 59:1–8PubMedCrossRefGoogle Scholar
  134. Murata T, Shimizu K, Hiramoto K, Tagawa T, Murata T, Shimizu K, Hiramoto K, Tagawa T (2009) Phosphodiesterase 3 (PDE3): structure, localization and function. Cardiovasc Hematol Agents Med Chem 7:206–211PubMedCrossRefGoogle Scholar
  135. Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD (2007) Isoform-selective susceptibility DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci 27:9513–9524PubMedCrossRefGoogle Scholar
  136. Nagel DJ, Aizawa T, Jeon KI, Liu W, Mohan A, Wei H (2006) Role of nuclear Ca2+/calmodulin-stimulated phos- phodiesterase 1A in vascular smooth muscle cell growth and survival. Circ Res 98:777–784PubMedCrossRefGoogle Scholar
  137. Navakkode S, Sajikumar S, Frey JU (2005) Mitogen-activated protein kinase-mediated reinforcement of hippocampal early long-term depression by the type IV-specific phosphodiesterase inhibitor rolipram and its effect on synaptic tagging. J Neurosci 25:10664–10670PubMedCrossRefGoogle Scholar
  138. Nguyen RV, Woo NH (2003) Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases. Prog Neurobiol 71:401–437PubMedCrossRefGoogle Scholar
  139. Nikolaev VO, Gambaryan S, Engehardt S, Walter U, Lohse MJ (2005) Real-time monitoring of the PDE2 a activity of live cells: hormone-stimulate camp hydrolysis is faster than hormone-stimulated cAMP synthesis. J Biol Chem 280:1716–1719PubMedCrossRefGoogle Scholar
  140. Numata S, Ueno S, Iga J, Song H, Nakataki M, Tayoshi S, Sumitani S, Tomotake M, Itakura M, Sano A, Ohmori TJ (2008) Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population. Psychiatr Res 43:7–12CrossRefGoogle Scholar
  141. O’Donnell JM, Zhang HT (2004) Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 25:158–163PubMedCrossRefGoogle Scholar
  142. Obara Y, Nakahata N, Stork PJ (2009) cAMP signaling for ERK activation in neuronal cells. Nippon Yakurigaku Zasshi 133:63–68PubMedCrossRefGoogle Scholar
  143. O’Conner MS, Steiner JM, Roussel AJ, Williams DA, Meddings JB, Pipers F, Cohen ND (2004) Evaluation of urine sucrose concentration for detection of gastric ulcers in horses. Am J Vet Res 65:31–39PubMedCrossRefGoogle Scholar
  144. Oike Y, Hata A, Mamiya T, Kaname T, Noda Y, Suzuki M, Yasue H, Nabeshima T, Araki K, Yamamura K (1999) Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum Mol Genet 8:387–396PubMedCrossRefGoogle Scholar
  145. Oliveira RF, Terrin A, Di Benedetto G, Cannon RC, Koh W, Kim M, Zaccolo M, Blackwell KT (2010) The role of type 4 Phosphodiesterases in generating microdomains of cAMP: large scale stochastic simulations. PLoS ONE 5:e11725PubMedCrossRefGoogle Scholar
  146. Olton DS (1983) Memory functions and the hippocampus. In: Seifert W (ed) Neurobiology of the hippcampus. Academic, London, pp 335–369Google Scholar
  147. Oray S, Majewska A, Sur M (2004) Dendritic spine dynamics are regulated by monocular deprivation and extracellular matrix degradation. Neuron 44:1021–1030PubMedCrossRefGoogle Scholar
  148. Paizanis E, Hamon M, Lanfumey L (2007) Hippocampal neurogenesis, depressive disorders, and antidepressant therapy. Neural Plast. 2007:737–754Google Scholar
  149. Palmer D, Jimmo SL, Raymond DR, Wilson LS, Carter RL, Maurice DH (2007) Protein kinase A phosphorylation of human phosphodiesterase 3B promotes 14-3-3 protein binding and inhibits phosphatase-catalyzed inactivation. J Biol Chem 282:9411–9419PubMedCrossRefGoogle Scholar
  150. Pause BM, Miranda A, Goder R, Aldenhoff JB, Ferstl R (2001) Reduced olfactory performance in patients with major depression. J Psychiatr Res 35:271–277PubMedCrossRefGoogle Scholar
  151. Pérez-Torres S, Miró X, Palacios JM, Puigdoménech P, Mengod G (2001) PDE4 isozymes expression in human brain examined by in situ hybridization histochemistry and rolipram binding sites. Comparison with monkey and rat brains. J Chem Neuroanat 20:349–374CrossRefGoogle Scholar
  152. Pelligrino DA, Wang Q (1998) Cyclic nucleotide crosstalk and the regulation of cerebral vasodilation. Prog Neurobiol 56:1–18PubMedCrossRefGoogle Scholar
  153. Pereira A Jr, Furlan FA (2010) Astrocytes and human cognition:Modeling information integration and modulation of neuronal activity. Neurobiology 1046:1–16Google Scholar
  154. Pérez-Torres S, Miró X, Palacios JM, Cortés R, Puigdoménech P, Mengod G (2000) Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and[3H]rolipram binding autoradiography. Comparison with monkey and rat brain. J Chem Neuroanat 20:349–374PubMedCrossRefGoogle Scholar
  155. Pérez-Torres S, Cortés R, Tolnay M, Probst A, Palacios JM, Mengod G (2003) Alteration of phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer’s disease brains examined by in situ hybridization. Exp Neurol 182:322–334PubMedCrossRefGoogle Scholar
  156. Pickard BS, Thomson PA, Christoforou A, Evans KL, Morris SW, Porteous DJ, Blackwood DH, Muir WJ (2007) The PDE4B gene confers sex-specific protection against schizophrenia. Psychiatr Genet 17:129–133PubMedCrossRefGoogle Scholar
  157. Pilz RB, Broderick KE (2005) Role of cyclic GMP in gene regulation. Front Biosci 10:1239–1268PubMedCrossRefGoogle Scholar
  158. Pollatos O, Kopietz R, Linn J, Albrecht J, Sakar V, Anzinger A, Schandry R, Wiesmann M (2007) Emotional stimulation alters olfactory sensitivity and odor judgment. Chem Senses 32:583–589PubMedCrossRefGoogle Scholar
  159. Prickaerts J, van Staveren WC, Sik A, Markerink-van Ittersum M, Niewöhner U, van der Staay FJ, Blokland A, de Vente J (2002) Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat. Neuroscience 113:351–361PubMedCrossRefGoogle Scholar
  160. Prickaerts J, Sik A, van Staveren WC, Koopmans G, Steinbusch HW, van der Staay FJ, de Vente J, Blokland A (2004) Phosphodiesterase type 5 inhibition improves early memory consolidation of object information. Neurochem Int 45:915–928PubMedCrossRefGoogle Scholar
  161. Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O (2005) Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci 25:6887–6897PubMedCrossRefGoogle Scholar
  162. Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O (2009) Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-load in an Alzheimer’s disease mouse model. J Neurosci 29:8075–8086PubMedCrossRefGoogle Scholar
  163. Pyne NJ, Cooper ME, Houslay MD (1986) Identification and characterization of both the cytosolic and particulate forms of cyclic GMP-stimulated cyclic AMP phosphodiesterase from rat liver. Biochem J 234:325–334PubMedGoogle Scholar
  164. Quiroz JA, Machado-Vieira R, Zarate CA Jr, Manji HK (2010) Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 62:50–60PubMedCrossRefGoogle Scholar
  165. Ramos BP, Birnbaum SG, Lindenmayer I, Newton SS, Duman RS, Arnsten AFT (2003) Dysregulation of protein kinase A signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 40:835–845PubMedCrossRefGoogle Scholar
  166. Ramos BP, Stark D, Verduzco L, van Dyck CH, Arnsten AF (2006) Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem 13:770–776PubMedCrossRefGoogle Scholar
  167. Rapoport M, van Reekum R, Mayberg H (2000) The role of the cerebellum in cognition and behavior: a selective review. J Neuropsychiatry Clin Neurosci 12:193–198PubMedCrossRefGoogle Scholar
  168. Reinés A, Cereseto M, Ferrero A, Sifonios L, Podestá MF, Wikinski S (2008) Maintenance treatment with fluoxetine is necessary to sustain normal levels of synaptic markers in an experimental model of depression: correlation with behavioral response. Neuropsychopharmacology 33:1896–1908PubMedCrossRefGoogle Scholar
  169. Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J (2009) Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology 202:419–443PubMedCrossRefGoogle Scholar
  170. Reyes-Irisarri E, Pérez-Torres S, Mengod G (2005) Neuronal expression of cAMP-specific phosphodiesterase 7B mRNA in the rat brain. Neuroscience 132:1173–1185PubMedCrossRefGoogle Scholar
  171. Rose GM, Hopper A, De Vivo M, Tehim A (2005) Phosphodiesterase inhibitors for cognitive enhancement. Curr Pharm Des 11:3329–3334PubMedCrossRefGoogle Scholar
  172. Rutten K, Prickaerts J, Blokland A (2006) Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by diVerent mechanisms of action. Neurobiol Learn Mem 85:132–138PubMedCrossRefGoogle Scholar
  173. Rutten K, Prickaerts J, Hendrix M, van der Staay FJ, Sik A, Blokland A (2007) Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 558:107–112PubMedCrossRefGoogle Scholar
  174. Rutten K, Misner DL, Works M, Blokland A, Novak TJ, Santarelli L, Wallace TL (2008) Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D) mice. Eur J Neurosci 28:625–632PubMedCrossRefGoogle Scholar
  175. Rybalkin SD, Rybalkina I, Beavo JA, Bornfeldt KE (2002) Cyclic nucleotide phosphodiesterase 1C promotes human J. of Cardiovasc. Trans. Res. J. of Cardiovasc. Trans. Res. arterial smooth muscle cell proliferation. Circ Res 90:151–157PubMedCrossRefGoogle Scholar
  176. Sasaki T, Yuasa K, Omori K (2000) Identification of human PDE7B, a cAMP specific phosphodiesterase. Biochem Biophys Res Comm 271:575–583PubMedCrossRefGoogle Scholar
  177. Sasaki T, Kotera J, Omori K (2002) Novel alternative splice variants of rat phosphodiesterase 7B showing unique tissue-specific expression and phosphorylation. Biochem J 361:211–220PubMedCrossRefGoogle Scholar
  178. Sasaki T, Kotera J, Omori K (2004) Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons. J Neurochem 89:474–483PubMedCrossRefGoogle Scholar
  179. Schaak S, Cayla C, Lymperopoulos A, Flordellis C, Cussac D, Denis C, Paris H (2000) Transcriptional down-regulation of the human alpha2C-adrenergic receptor by cAMP. Mol Pharmacol 58:821–827PubMedGoogle Scholar
  180. Schmidt CJ (2010) Phosphodiesterase inhibitors as potential cognition enhancing agents. Curr Top Med Chem 10:222–230PubMedCrossRefGoogle Scholar
  181. Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, Lanfear J, Ryan AM, Schmidt CJ, Strick CA, Varghese AH, Williams RD, Wylie PG, Menniti FS (2003) Immunohistochemical localization of PDE10A in the rat brain. Brain Res 985:113–126PubMedCrossRefGoogle Scholar
  182. Sette C, Iona S, Conti M (1994) The short-term activation of a rolipramsensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation. J Biol Chem 269:9245–9252PubMedGoogle Scholar
  183. Singh N, Parle M (2003) Sildenafil improves acquisition and retention of memory in mice. Indian J Physiol Pharmacol 47:318–324PubMedGoogle Scholar
  184. Siuciak JA (2008) The role of phosphodiesterases in schizophrenia: therapeutic implications. CNS Drugs 22:983–993PubMedCrossRefGoogle Scholar
  185. Siuciak JA, McCarthy SA, Chapin DS, Fujiwara RA, James LC, Williams RD, Stock JL, McNeish JD, Strick CA, Menniti FS, Schmidt CJ (2006) Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. Neuropharmacology 51:374–385PubMedCrossRefGoogle Scholar
  186. Siuciak JA, Chapin DS, McCarthy SA, Martin AN (2007) Antipsychoticprofole of rolipram: efficacy in rat and reduced sensitivity in mice deficient in the phosphodiesterase-4B(PDE4B) enzyme. Psychopharmacology (Berl) 192:415–424CrossRefGoogle Scholar
  187. Siuciak JA, McCarthy SA, Chapin DS, Martin AN (2008) Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology 197:115–126PubMedCrossRefGoogle Scholar
  188. Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES (2002) Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry 7:579–593PubMedCrossRefGoogle Scholar
  189. Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG, Barnes PJ, Barnette MS, Giembycz MA (2004) Discovery of BRL 50481 [3-(N, N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol Pharmacol 66:1679–1689PubMedCrossRefGoogle Scholar
  190. Soderling SH, Bayuga SJ, Beavo JA (1999) Isolation and characterization of a dual-substrated phosphodiesterase gene family: PDE10A. Proc Natl Acad Sci USA 96:7071–7076PubMedCrossRefGoogle Scholar
  191. Souness JE, Aldous D, Sargent C (2000) Immunosuppressive and antiinfl ammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology 47:127–162PubMedCrossRefGoogle Scholar
  192. Ster J, de Bock F, Bertaso F, Abitbol K, Daniel H, Bockaert J, Fagni L (2009) Epac mediates PACAP-dependent long-term depression in the hippocampus. J Physiol 587:101–113PubMedCrossRefGoogle Scholar
  193. Strick CA, James LC, Fox CB, Seeger TF, Menniti FS, Schmidt CJ (2010) Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A. Neuropharmacology 58:444–451PubMedCrossRefGoogle Scholar
  194. Surapisitchat J, Jeon KI, Yan C, Beavo JA (2007) Differential regulation of endothelial cell permeability by cGMP via phosphodiesterases 2 and 3. Circ Res 101:811–818PubMedCrossRefGoogle Scholar
  195. Suvarna NU, O’Donnell JM (2002) Hydrolysis of N-methyl-D-aspartate receptor-stimulated cAMP and cGMP by PDE4 and PDE2 phosphodiesterases in primary neuronal cultures of rat cerebral cortex and hippocampus. J Pharmacol Exp Ther 302:249–256PubMedCrossRefGoogle Scholar
  196. Takahashi M, Terwilliger R, Lane C, Mezes PS, Conti M, Duman RS (1999) Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms. J Neurosci 19:610–618PubMedGoogle Scholar
  197. Tanis KQ, Duman RS (2007) Intracellular signaling pathways pave roads to recovery for mood disorders. Ann Med 39:531–544PubMedCrossRefGoogle Scholar
  198. Taylor JR, Birnbaum SG, Ubriani R, Arnsten AFT (1999) Activation of protein kinase A in prefrontal cortex impairs working memory performance. J Neurosci 19:RC23PubMedGoogle Scholar
  199. Taylor RE, Shows KH, Zhao Y, Pittler SJ (2001) A PDE6A promoter fragment directs transcription predominantly in the photoreceptor. Biochem Biophys Res Commun 282:543–547PubMedCrossRefGoogle Scholar
  200. Teng FY, Tang BL (2006) Axonal regeneration in adult CNS neurons-signaling molecules and pathways. J Neurochem 96:1501–1508PubMedCrossRefGoogle Scholar
  201. Thompson PE, Manganiello V, Degerman E (2007) Re-discovering PDE3 inhibitors – new opportunities for a long neglected target. Curr Top Med Chem 7:421–436PubMedCrossRefGoogle Scholar
  202. Titus SA, Li X, Southall N, Lu J, Inglese J, Brasch M, Austin CP, Zheng W (2008) A cell-based PDE4 assay in 1536-well plate format for high-throughput screening. J Biomol Screen 13:609–618PubMedCrossRefGoogle Scholar
  203. Torras-Llort M, Azorin F (2003) Functional characterization of the human phosphodiesterase 7A1 promoter. Biochem J 373:835–843PubMedCrossRefGoogle Scholar
  204. Uthayathas S, Karuppagounder SS, Thrash BM, Parameshwaran K, Suppiramaniam V, Dhanasekaran M (2007) Versatile effects of sildenafil: recent pharmacological applications. Pharmacol Rep 59:150–163PubMedGoogle Scholar
  205. Valera E, Sánchez-Martín FJ, Ferrer-Montiel AV, Messeguer A, Merino JM (2008) NMDA-induced neuroprotection in hippocampal neurons is mediated through the protein kinase A and CREB (cAMP-response element-binding protein) pathway. Neurochem Int 58:148–154CrossRefGoogle Scholar
  206. Van der Staay FJ, Rutten K, Bärfacker L, Devry J, Erb C, Heckroth H, Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J, Reymann KG, Schröder UH, Hendrix M (2008) The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology 55:908–918PubMedCrossRefGoogle Scholar
  207. van Donkelaar EL, Rutten K, Blokland A, Akkerman S, Steinbusch HW, Prickaerts J (2008) Phosphodiesterase 2 and 5 inhibition attenuates the object memory deficit induced by acute tryptophan depletion. Eur J Pharmacol 600:98–104PubMedCrossRefGoogle Scholar
  208. Van Staveren WCG, Markerink-Van Ittersum M, Steinbusch HWM, De Vente J (2001) The effect of phosphodiesterase inhibition on cyclic GMP and cyclic AMP accumulation in the hippocampus of the rat. Brain Res 888:275–286PubMedCrossRefGoogle Scholar
  209. Van Staveren WC, Steinbusch HW, Markerink-van Ittersum M, Repaske DR, Goy MF, Kotera J, Omori K, Beavo JA, De Vente J (2003) mRNA expression patterns of the cGMP-hydrolyzing phosphodiester- ases types 2, 5, and 9 during development of the rat brain. J Comp Neurol 467:566–580PubMedCrossRefGoogle Scholar
  210. Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, Huang T, Brown KM, Li XY, Descalzi G, Kim SS, Chen T, Shang YZ, Zhuo M, Houslay MD, Abel T (2009) Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 461:1122–1125PubMedCrossRefGoogle Scholar
  211. Viana RJ, Fonseca MB, Ramalho RM, Nunes AF, Rodrigues CM (2010) Organelle stress sensors and cell death mechanisms in neurodegenerative diseases. CNS Neurol Disord Drug Targets 9(6):679–692PubMedGoogle Scholar
  212. Wachtel H (1982) Characteristic behavioural alterations in rats induced by rolipram and other selective adenosine cyclic 3', 5'-monophosphate phosphodiesterase inhibitors. Psychopharmacol (Berl) 77:309–316CrossRefGoogle Scholar
  213. Weeks JL, Zoraghi R, Francis SH, Corbin JD (2007) N-Terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is involved in oligomerization. Biochemistry 46:10353–10364PubMedCrossRefGoogle Scholar
  214. Whitaker CM, Wei H (2009) An alternate cAMP pathway Epac promotes hippocampal long-term depression. J Physiol 587:3067–3068PubMedCrossRefGoogle Scholar
  215. Wong ML, Whelan F, Deloukas P, Whittaker P, Delgado M, Cantor RM, McCann SM, Licinio J (2006) Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proc Natl Acad Sci USA 103:15124–15129PubMedCrossRefGoogle Scholar
  216. Woolfrey KM, Srivastava DP, Photowala H, Yamashita M, Barbolina MV, Cahill ME, Xie Z, Jones KA, Quilliam LA, Prakriya M, Penzes P (2009) Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci 12:1275–1284PubMedCrossRefGoogle Scholar
  217. Wu AY, Tang XB, Martinez SE, Ikeda K, Beavo JA (2004) Molecular determinants for cyclic nucleotide binding to the regulatory domains of phosphodiesterase 2A. J Biol Chem 279:37928–37938PubMedCrossRefGoogle Scholar
  218. Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M (2005) Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol Pharmacol 68:1775–1781PubMedGoogle Scholar
  219. Xie Z, Adamowicz WO, Eldred WD, Jakowski AB, Kleiman RJ, Morton DG, Stephenson DT, Strick CA, Williams RD, Menniti F (2006) Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Neuroscience 139:597–607PubMedCrossRefGoogle Scholar
  220. Yang G, McIntyre KW, Townsend RM, Shen HH, Pitts WJ, Dodd JH, Nadler SG, McKinnon M, Watson AJ (2003) Phosphodiesterase 7A-deficient mice have functional T cells. J Immunol 171:6414–6420PubMedGoogle Scholar
  221. Yuasa K, Kanoh Y, Okumura K, Omori K (2001) Genomic organization of the human phosphodiesterase PDE11A gene, Evolutionary relatedness with other PDEs containing GAF domains. Eur J Biochem 268:168–178PubMedCrossRefGoogle Scholar
  222. Zaccolo M, Movsesian MA (2007) cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res 100:1569–1578PubMedCrossRefGoogle Scholar
  223. Zhan Y, Zhang HT, O’Donnel JM (2003) Antidepressant-induced increase in high-affinity rolipram binding sites in rat brain: dependence on noradrenergic and serotonergic function. J Pharmacol Exp Ther 307:246–253CrossRefGoogle Scholar
  224. Zhang HT (2009) Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 15:1687–1698Google Scholar
  225. Zhang HT, O’Donnell JM (2000) Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology 150:311–316PubMedCrossRefGoogle Scholar
  226. Zhang HT, Crissman AM, Dorairaj NR, Chandler LJ, O’Donnell JM (2000) Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 23:198–204PubMedCrossRefGoogle Scholar
  227. Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M, O'Donnell JM (2002a) Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27:587–595PubMedGoogle Scholar
  228. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M (2002b) Sildenafi l (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33:2675–2680PubMedCrossRefGoogle Scholar
  229. Zhang HT, Zhao Y, Huang Y, Dorairaj NR, Chandler LJ, O’Donnell JM (2004) Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Neuropsychopharmacology 29:1432–1439PubMedCrossRefGoogle Scholar
  230. Zhang HT, Huang Y, Suvarna NU, Deng C, Crissman AM, Hopper AT, De Vivo M, Rose GM, O'Donnell JM (2005) Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology 179:613–619PubMedCrossRefGoogle Scholar
  231. Zhang L, Zhang Z, Zhang RL, Cui Y, LaPointe MC, Silver B, Chopp M (2006) Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res 1118:192–198PubMedCrossRefGoogle Scholar
  232. Zhang HT, Huang Y, Masood A, Stolinski LR, Li Y, Zhang L, Dlaboga D, Jin SL, Conti M, O’Donnell JM (2008) Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 33:1611–1623PubMedCrossRefGoogle Scholar
  233. Zhao J, Harada N, Kurihara H, Nakagata N, Okajima K (2010) Cilostazol improves cognitive function in mice by increasing the production of insulin-like growth factor-I in the hippocampus. Neuropharmacology 58:774–783PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Ying Xu
    • 1
  • Han-Ting Zhang
    • 1
  • James M. O’Donnell
    • 1
    Email author
  1. 1.Departments of Behavioral Medicine & Psychiatry, Neurobiology & Anatomy, and Physiology & Pharmacology and the WVU Center for NeuroscienceWest Virginia University Health Sciences Center, WVU HSC/School of MedicineMorgantownUSA

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