Psychopharmacology

, Volume 219, Issue 4, pp 1065–1079 | Cite as

Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex

  • Mahomi Kuroiwa
  • Gretchen L. Snyder
  • Takahide Shuto
  • Atsuo Fukuda
  • Yuchio Yanagawa
  • David R. Benavides
  • Angus C. Nairn
  • James A. Bibb
  • Paul Greengard
  • Akinori Nishi
Original Investigation

Abstract

Rationale

Alteration of dopamine neurotransmission in the prefrontal cortex, especially hypofunction of dopamine D1 receptors, contributes to psychotic symptoms and cognitive deficit in schizophrenia. D1 receptors signal through the cAMP/PKA second messenger cascade, which is modulated by phosphodiesterase (PDE) enzymes that hydrolyze and inactivate cyclic nucleotides. Though several PDEs are expressed in cortical neurons, the PDE4 enzyme family (PDE4A-D) has been implicated in the control of cognitive function. The best studied isoform, PDE4B, interacts with a schizophrenia susceptibility factor, disrupted in schizophrenia 1 (DISC1).

Objectives

We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4.

Results

Inhibition of PDE4 by rolipram induced activation of cAMP/PKA signaling in cortical slices and in vivo, leading to the phosphorylation of DARPP-32 and other postsynaptic and presynaptic PKA-substrates. Rolipram also enhanced DARPP-32 phosphorylation invoked by D1 receptor activation. Immunohistochemical studies demonstrated PDE4A, PDE4B, and PDE4D expression in DARPP-32-positive neurons in layer VI of frontal cortex, most likely in D1 receptor-positive, glutamatergic corticothalamic pyramidal neurons. Furthermore, the ability of rolipram treatment to improve the performance of mice in a sensorimotor gating test was DARPP-32-dependent.

Conclusions

PDE4, which is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons in layer VI, modulates the level of D1 receptor signaling and DARPP-32 phosphorylation in the frontal cortex, likely influencing cognitive function. These biochemical and behavioral actions of PDE4 inhibitors may contribute to the hypothesized antipsychotic actions of this class of compounds.

Keywords

PDE4 DARPP-32 PKA Frontal cortex Prepulse inhibition Rolipram 

Supplementary material

213_2011_2436_MOESM1_ESM.doc (5 mb)
Online Resource 1Expression of PDE4 subtypes in the cortex. Double immunostaining of mouse cortical tissues with DARPP-32 and PDE4A (a), PDE4C (b), or PDE4D (c, d) antibodies. High magnification pictures of cingulate cortex: area 1 for PDE4A (a, inset) and PDE4D (d) staining are shown. Scale bars, 50 mm for ac and 10 mm for ainset and d (DOC 5094 kb)

References

  1. Ahn JH, McAvoy T, Rakhilin SV, Nishi A, Greengard P, Nairn AC (2007) Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. Proc Natl Acad Sci USA 104:2979–2984PubMedCrossRefGoogle Scholar
  2. Albert KA, Hemmings HC Jr, Adamo AI, Potkin SG, Akbarian S, Sandman CA, Cotman CW, Bunney WE Jr, Greengard P (2002) Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia. Arch Gen Psychiatry 59:705–712PubMedCrossRefGoogle Scholar
  3. Alvarez R, Sette C, Yang D, Eglen RM, Wilhelm R, Shelton ER, Conti M (1995) Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE-4D3. Mol Pharmacol 48:616–622PubMedGoogle Scholar
  4. Bateup HS, Svenningsson P, Kuroiwa M, Gong S, Nishi A, Heintz N, Greengard P (2008) Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs. Nat Neurosci 11:932–939PubMedCrossRefGoogle Scholar
  5. Beavo JA (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms [Review]. Physiol Rev 75:725–748PubMedGoogle Scholar
  6. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520PubMedCrossRefGoogle Scholar
  7. Berger B, Febvret A, Greengard P, Goldman-Rakic P (1990) DARPP-32, a phosphoprotein enriched in dopaminoceptive neurons bearing dopamine D1 receptor: distribution in the cerebral cortex of the newborn and adult rhesus monkey. J Comp Neurol 299:327–348PubMedCrossRefGoogle Scholar
  8. Bergson C, Mrzljak L, Smiley JF, Pappy M, Levenson R, Goldman-Rakic PS (1995) Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain. J Neurosci 15:7821–7836PubMedGoogle Scholar
  9. Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC, Greengard P (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402:669–671CrossRefGoogle Scholar
  10. Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156:234–258CrossRefGoogle Scholar
  11. Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME (2010) Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28:63–70PubMedCrossRefGoogle Scholar
  12. Castro LR, Gervasi N, Guiot E, Cavellini L, Nikolaev VO, Paupardin-Tritsch D, Vincent P (2010) Type 4 phosphodiesterase plays different integrating roles in different cellular domains in pyramidal cortical neurons. J Neurosci 30:6143–6151PubMedCrossRefGoogle Scholar
  13. Chen BS, Roche KW (2007) Regulation of NMDA receptors by phosphorylation. Neuropharmacology 53:362–368PubMedCrossRefGoogle Scholar
  14. Cherry JA, Davis RL (1999) Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol 407:287–301PubMedCrossRefGoogle Scholar
  15. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13:36–64PubMedCrossRefGoogle Scholar
  16. Chudasama Y, Robbins TW (2004) Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 29:1628–1636PubMedCrossRefGoogle Scholar
  17. 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
  18. 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
  19. Doherty JM, Masten VL, Powell SB, Ralph RJ, Klamer D, Low MJ, Geyer MA (2008) Contributions of dopamine D1, D2, and D3 receptor subtypes to the disruptive effects of cocaine on prepulse inhibition in mice. Neuropsychopharmacology 33:2648–2656PubMedCrossRefGoogle Scholar
  20. Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW (2004) Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 91:1025–1043PubMedCrossRefGoogle Scholar
  21. Ehrman LA, Williams MT, Schaefer TL, Gudelsky GA, Reed TM, Fienberg AA, Greengard P, Vorhees CV (2006) Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice. Genes Brain Behav 5:540–551PubMedCrossRefGoogle Scholar
  22. 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
  23. Fienberg AA, Hiroi N, Mermelstein P, Song W-J, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller D, Cole D, Corbett R, Haile C, Cooper D, Onn S, Grace AA, Ouimet C, White FJ, Hyman SE, Surmeier DJ, Girault JA, Nestler E, Greengard P (1998) DARPP-32, regulator of the efficacy of dopaminergic neurotransmission. Science 281:838–842PubMedCrossRefGoogle Scholar
  24. Fiumara F, Giovedi S, Menegon A, Milanese C, Merlo D, Montarolo PG, Valtorta F, Benfenati F, Ghirardi M (2004) Phosphorylation by cAMP-dependent protein kinase is essential for synapsin-induced enhancement of neurotransmitter release in invertebrate neurons. J Cell Sci 117:5145–5154PubMedCrossRefGoogle Scholar
  25. Fletcher PJ, Tenn CC, Rizos Z, Lovic V, Kapur S (2005) Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Psychopharmacology (Berl) 183:190–200CrossRefGoogle Scholar
  26. Fukuda T, Aika Y, Heizmann CW, Kosaka T (1996) Dense GABAergic input on somata of parvalbumin-immunoreactive GABAergic neurons in the hippocampus of the mouse. Neurosci Res 26:181–194PubMedCrossRefGoogle Scholar
  27. Gaspar P, Bloch B, Le Moine C (1995) D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons. Eur J Neurosci 7:1050–1063PubMedCrossRefGoogle Scholar
  28. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156:117–154CrossRefGoogle Scholar
  29. Geyer MA, McIlwain KL, Paylor R (2002) Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry 7:1039–1053PubMedCrossRefGoogle Scholar
  30. Goldman-Rakic PS, Lidow MS, Gallager DW (1990) Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex. J Neurosci 10:2125–2138PubMedGoogle Scholar
  31. Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV (2004) Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 174:3–16CrossRefGoogle Scholar
  32. Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435–447PubMedCrossRefGoogle Scholar
  33. Harada K, Wu J, Haycock JW, Goldstein M (1996) Regulation of L-DOPA biosynthesis by site-specific phosphorylation of tyrosine hydroxylase in AtT-20 cells expressing wild-type and serine 40-substituted enzyme. J Neurochem 67:629–635PubMedCrossRefGoogle Scholar
  34. Hebb AL, 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
  35. Hoffmann R, Wilkinson IR, McCallum JF, Engels P, Houslay MD (1998) cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J 333(Pt 1):139–149PubMedGoogle Scholar
  36. Hotte M, Thuault S, Lachaise F, Dineley KT, Hemmings HC, Nairn AC, Jay TM (2006) D1 receptor modulation of memory retrieval performance is associated with changes in pCREB and pDARPP-32 in rat prefrontal cortex. Behav Brain Res 171:127–133PubMedCrossRefGoogle Scholar
  37. Hotte M, Thuault S, Dineley KT, Hemmings HC Jr, Nairn AC, Jay TM (2007) Phosphorylation of CREB and DARPP-32 during late LTP at hippocampal to prefrontal cortex synapses in vivo. Synapse 61:24–28PubMedCrossRefGoogle Scholar
  38. Houslay MD (2010) Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 35:91–100PubMedCrossRefGoogle Scholar
  39. Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370:1–18PubMedCrossRefGoogle Scholar
  40. Houslay MD, Schafer P, Zhang KY (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10:1503–1519PubMedCrossRefGoogle Scholar
  41. Huang Z, Mancini JA (2006) Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD. Curr Med Chem 13:3253–3262PubMedCrossRefGoogle Scholar
  42. Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP (2007) Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity. Neuroscience 144:239–246PubMedCrossRefGoogle Scholar
  43. 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
  44. McCahill AC, Huston E, Li X, Houslay MD (2008) PDE4 associates with different scaffolding proteins: modulating interactions as treatment for certain diseases. Handb Exp Pharmacol: 125–66Google Scholar
  45. McPhee I, Yarwood SJ, Scotland G, Huston E, Beard MB, Ross AH, Houslay ES, Houslay MD (1999) Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition. J Biol Chem 274:11796–11810PubMedCrossRefGoogle Scholar
  46. Menniti FS, Faraci WS, Schmidt CJ (2006) Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5:660–670PubMedCrossRefGoogle Scholar
  47. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310:1187–1191PubMedCrossRefGoogle Scholar
  48. 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
  49. Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD (2007) Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci 27:9513–9524PubMedCrossRefGoogle Scholar
  50. Nishi A, Snyder GL (2010) Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: biochemical and behavioral profiles of phosphodiesterase inhibition in dopaminergic neurotransmission. J Pharmacol Sci 114:6–16PubMedCrossRefGoogle Scholar
  51. Nishi A, Kuroiwa M, Miller DB, O'Callaghan JP, Bateup HS, Shuto T, Sotogaku N, Fukuda T, Heintz N, Greengard P, Snyder GL (2008) Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci 28:10460–10471PubMedCrossRefGoogle Scholar
  52. Noyama K, Maekawa S (2003) Localization of cyclic nucleotide phosphodiesterase 2 in the brain-derived Triton-insoluble low-density fraction (raft). Neurosci Res 45:141–148PubMedCrossRefGoogle Scholar
  53. Numata S, Ueno S, Iga J, Song H, Nakataki M, Tayoshi S, Sumitani S, Tomotake M, Itakura M, Sano A, Ohmori T (2008) Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population. J Psychiatr Res 43:7–12PubMedCrossRefGoogle Scholar
  54. O'Callaghan JP, Sriram K (2004) Focused microwave irradiation of the brain preserves in vivo protein phosphorylation: comparison with other methods of sacrifice and analysis of multiple phosphoproteins. J Neurosci Methods 135:159–168PubMedCrossRefGoogle Scholar
  55. Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, Toru M (1997) Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 385:634–636PubMedCrossRefGoogle Scholar
  56. Ouimet CC (1991) DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein, is present in corticothalamic neurons of the rat cingulate cortex. Brain Res 562:85–92PubMedCrossRefGoogle Scholar
  57. Ouimet CC, Miller PE, Hemmings HC Jr, Walaas SI, Greengard P (1984) DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J Neurosci 4:114–124Google Scholar
  58. Ouimet CC, LaMantia AS, Goldman-Rakic P, Rakic P, Greengard P (1992) Immunocytochemical localization of DARPP-32, a dopamine and cyclic-AMP-regulated phosphoprotein, in the primate brain. J Comp Neurol 323:209–218PubMedCrossRefGoogle Scholar
  59. 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
  60. Ralph RJ, Caine SB (2005) Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion: comparison of Sprague-Dawley rats to Swiss-Webster, 129X1/SvJ, C57BL/6J, and DBA/2J mice. J Pharmacol Exp Ther 312:733–741PubMedCrossRefGoogle Scholar
  61. Ralph RJ, Paulus MP, Fumagalli F, Caron MG, Geyer MA (2001) Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J Neurosci 21:305–313PubMedGoogle Scholar
  62. Ralph-Williams RJ, Lehmann-Masten V, Otero-Corchon V, Low MJ, Geyer MA (2002) Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice. J Neurosci 22:9604–9611PubMedGoogle Scholar
  63. Ralph-Williams RJ, Lehmann-Masten V, Geyer MA (2003) Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice. Neuropsychopharmacology 28:108–118PubMedCrossRefGoogle Scholar
  64. Roche KW, O'Brien RJ, Mammen AL, Bernhardt J, Huganir RL (1996) Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16:1179–1188PubMedCrossRefGoogle Scholar
  65. Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950PubMedCrossRefGoogle Scholar
  66. 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
  67. Sette C, Conti M (1996) Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation. J Biol Chem 271:16526–16534PubMedCrossRefGoogle Scholar
  68. Siuciak JA (2008) The role of phosphodiesterases in schizophrenia: therapeutic implications. CNS Drugs 22:983–993PubMedCrossRefGoogle Scholar
  69. Siuciak JA, Chapin DS, McCarthy SA, Martin AN (2007) Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 192:415–424CrossRefGoogle Scholar
  70. Siuciak JA, McCarthy SA, Chapin DS, Martin AN (2008) Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 197:115–126CrossRefGoogle Scholar
  71. Souness JE, Rao S (1997) Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 9:227–236PubMedCrossRefGoogle Scholar
  72. Svenningsson P, Tzavara ET, Carruthers R, Rachleff I, Wattler S, Nehls M, McKinzie DL, Fienberg AA, Nomikos GG, Greengard P (2003) Diverse psychotomimetics act through a common signaling pathway. Science 302:1412–1415PubMedCrossRefGoogle Scholar
  73. Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P (2004) DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 44:269–296PubMedCrossRefGoogle Scholar
  74. Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156:194–215CrossRefGoogle Scholar
  75. Swerdlow NR, Light GA, Cadenhead KS, Sprock J, Hsieh MH, Braff DL (2006) Startle gating deficits in a large cohort of patients with schizophrenia: relationship to medications, symptoms, neurocognition, and level of function. Arch Gen Psychiatry 63:1325–1335PubMedCrossRefGoogle Scholar
  76. Tamamaki N, Yanagawa Y, Tomioka R, Miyazaki J, Obata K, Kaneko T (2003) Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol 467:60–79PubMedCrossRefGoogle Scholar
  77. Tamminga CA (2006) The neurobiology of cognition in schizophrenia. J Clin Psychiatry 67(Suppl 9):9–13, discussion 36–42PubMedGoogle Scholar
  78. Tanda K, Nishi A, Matsuo N, Nakanishi K, Yamasaki N, Sugimoto T, Toyama K, Takao K, Miyakawa T (2009) Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice. Mol Brain 2:19PubMedCrossRefGoogle Scholar
  79. Walaas SI, Greengard P (1984) DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular disrtribution in rat brain. J Neurosci 4:84–98PubMedGoogle Scholar
  80. Zhang HT (2009) Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 15:1688–1698PubMedCrossRefGoogle Scholar
  81. Zhu J, Mix E, Winblad B (2001) The antidepressant and antiinflammatory effects of rolipram in the central nervous system. CNS Drug Rev 7:387–398PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Mahomi Kuroiwa
    • 1
    • 2
  • Gretchen L. Snyder
    • 3
  • Takahide Shuto
    • 1
    • 2
  • Atsuo Fukuda
    • 4
  • Yuchio Yanagawa
    • 2
    • 5
  • David R. Benavides
    • 6
  • Angus C. Nairn
    • 7
    • 8
  • James A. Bibb
    • 6
  • Paul Greengard
    • 8
  • Akinori Nishi
    • 1
    • 2
    • 8
  1. 1.Department of PharmacologyKurume University School of MedicineKurumeJapan
  2. 2.Japan Science of Technology AgencyCRESTTokyoJapan
  3. 3.Intra-Cellular Therapies, IncNew YorkUSA
  4. 4.Department of PhysiologyHamamatsu University School of MedicineHamamatsuJapan
  5. 5.Department of Genetic and Behavioral NeuroscienceGunma University Graduate School of MedicineMaebashiJapan
  6. 6.Department of PsychiatryThe University of Texas Southwestern Medical CenterDallasUSA
  7. 7.Department of PsychiatryYale University School of MedicineNew HavenUSA
  8. 8.Laboratory of Molecular and Cellular NeuroscienceThe Rockefeller UniversityNew YorkUSA

Personalised recommendations