Skip to main content
Springer Nature Link
Log in

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

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  • 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 104:2979–2984

    Article  PubMed  CAS  Google Scholar 

  • 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 59:705–712

    Article  PubMed  CAS  Google Scholar 

  • 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 48:616–622

    PubMed  CAS  Google Scholar 

  • 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 11:932–939

    Article  PubMed  CAS  Google Scholar 

  • Beavo JA (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms [Review]. Physiol Rev 75:725–748

    PubMed  CAS  Google Scholar 

  • Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520

    Article  PubMed  CAS  Google Scholar 

  • 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 299:327–348

    Article  PubMed  CAS  Google Scholar 

  • 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 15:7821–7836

    PubMed  CAS  Google Scholar 

  • 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 402:669–671

    Article  CAS  Google Scholar 

  • Braff DL, Geyer MA, Swerdlow NR (2001) Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl) 156:234–258

    Article  CAS  Google Scholar 

  • 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 28:63–70

    Article  PubMed  CAS  Google Scholar 

  • 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 30:6143–6151

    Article  PubMed  CAS  Google Scholar 

  • Chen BS, Roche KW (2007) Regulation of NMDA receptors by phosphorylation. Neuropharmacology 53:362–368

    Article  PubMed  Google Scholar 

  • 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 407:287–301

    Article  PubMed  CAS  Google Scholar 

  • Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13:36–64

    Article  PubMed  CAS  Google Scholar 

  • Chudasama Y, Robbins TW (2004) Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 29:1628–1636

    Article  PubMed  CAS  Google Scholar 

  • 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 54:387–402

    Article  PubMed  CAS  Google Scholar 

  • Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511

    Article  PubMed  CAS  Google Scholar 

  • 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 33:2648–2656

    Article  PubMed  CAS  Google Scholar 

  • Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW (2004) Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 91:1025–1043

    Article  PubMed  CAS  Google Scholar 

  • 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 5:540–551

    Article  PubMed  CAS  Google Scholar 

  • 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 101:36–49

    Article  PubMed  Google Scholar 

  • 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 281:838–842

    Article  PubMed  CAS  Google Scholar 

  • 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 117:5145–5154

    Article  PubMed  CAS  Google Scholar 

  • 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) 183:190–200

    Article  CAS  Google Scholar 

  • 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 26:181–194

    Article  PubMed  CAS  Google Scholar 

  • 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 7:1050–1063

    Article  PubMed  CAS  Google Scholar 

  • 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) 156:117–154

    Article  CAS  Google Scholar 

  • Geyer MA, McIlwain KL, Paylor R (2002) Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry 7:1039–1053

    Article  PubMed  CAS  Google Scholar 

  • 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 10:2125–2138

    PubMed  CAS  Google Scholar 

  • 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) 174:3–16

    Article  CAS  Google Scholar 

  • Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435–447

    Article  PubMed  CAS  Google Scholar 

  • 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 67:629–635

    Article  PubMed  CAS  Google Scholar 

  • 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 123:967–981

    Article  PubMed  CAS  Google Scholar 

  • 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):139–149

    PubMed  CAS  Google Scholar 

  • 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 171:127–133

    Article  PubMed  CAS  Google Scholar 

  • 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 61:24–28

    Article  PubMed  CAS  Google Scholar 

  • Houslay MD (2010) Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 35:91–100

    Article  PubMed  CAS  Google Scholar 

  • Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370:1–18

    Article  PubMed  CAS  Google Scholar 

  • Houslay MD, Schafer P, Zhang KY (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10:1503–1519

    Article  PubMed  CAS  Google Scholar 

  • Huang Z, Mancini JA (2006) Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD. Curr Med Chem 13:3253–3262

    Article  PubMed  CAS  Google Scholar 

  • Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP (2007) Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity. Neuroscience 144:239–246

    Article  PubMed  CAS  Google Scholar 

  • 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 136:421–433

    Article  PubMed  CAS  Google Scholar 

  • 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: 125–66

  • 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 274:11796–11810

    Article  PubMed  CAS  Google Scholar 

  • Menniti FS, Faraci WS, Schmidt CJ (2006) Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5:660–670

    Article  PubMed  CAS  Google Scholar 

  • 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 310:1187–1191

    Article  PubMed  CAS  Google Scholar 

  • 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 584:401–405

    Article  PubMed  CAS  Google Scholar 

  • 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 27:9513–9524

    Article  PubMed  CAS  Google Scholar 

  • 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 114:6–16

    Article  PubMed  CAS  Google Scholar 

  • 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 28:10460–10471

    Article  PubMed  CAS  Google Scholar 

  • Noyama K, Maekawa S (2003) Localization of cyclic nucleotide phosphodiesterase 2 in the brain-derived Triton-insoluble low-density fraction (raft). Neurosci Res 45:141–148

    Article  PubMed  CAS  Google Scholar 

  • 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 43:7–12

    Article  PubMed  Google Scholar 

  • 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 135:159–168

    Article  PubMed  Google Scholar 

  • 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 385:634–636

    Article  PubMed  CAS  Google Scholar 

  • Ouimet CC (1991) DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein, is present in corticothalamic neurons of the rat cingulate cortex. Brain Res 562:85–92

    Article  PubMed  CAS  Google Scholar 

  • 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 4:114–124

    Google Scholar 

  • 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 323:209–218

    Article  PubMed  CAS  Google Scholar 

  • 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 17:129–133

    Article  PubMed  Google Scholar 

  • 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 312:733–741

    Article  PubMed  CAS  Google Scholar 

  • 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 21:305–313

    PubMed  CAS  Google Scholar 

  • 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 22:9604–9611

    PubMed  CAS  Google Scholar 

  • Ralph-Williams RJ, Lehmann-Masten V, Geyer MA (2003) Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice. Neuropsychopharmacology 28:108–118

    Article  PubMed  CAS  Google Scholar 

  • Roche KW, O'Brien RJ, Mammen AL, Bernhardt J, Huganir RL (1996) Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16:1179–1188

    Article  PubMed  CAS  Google Scholar 

  • Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950

    Article  PubMed  CAS  Google Scholar 

  • 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 985:113–126

    Article  PubMed  CAS  Google Scholar 

  • 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 271:16526–16534

    Article  PubMed  CAS  Google Scholar 

  • Siuciak JA (2008) The role of phosphodiesterases in schizophrenia: therapeutic implications. CNS Drugs 22:983–993

    Article  PubMed  CAS  Google Scholar 

  • 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) 192:415–424

    Article  CAS  Google Scholar 

  • Siuciak JA, McCarthy SA, Chapin DS, Martin AN (2008) Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 197:115–126

    Article  CAS  Google Scholar 

  • Souness JE, Rao S (1997) Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 9:227–236

    Article  PubMed  CAS  Google Scholar 

  • 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 302:1412–1415

    Article  PubMed  CAS  Google Scholar 

  • Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P (2004) DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 44:269–296

    Article  PubMed  CAS  Google Scholar 

  • 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) 156:194–215

    Article  CAS  Google Scholar 

  • 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 63:1325–1335

    Article  PubMed  Google Scholar 

  • 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 467:60–79

    Article  PubMed  CAS  Google Scholar 

  • Tamminga CA (2006) The neurobiology of cognition in schizophrenia. J Clin Psychiatry 67(Suppl 9):9–13, discussion 36–42

    PubMed  CAS  Google Scholar 

  • 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 2:19

    Article  PubMed  Google Scholar 

  • 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 4:84–98

    PubMed  CAS  Google Scholar 

  • Zhang HT (2009) Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 15:1688–1698

    Article  PubMed  CAS  Google Scholar 

  • Zhu J, Mix E, Winblad B (2001) The antidepressant and antiinflammatory effects of rolipram in the central nervous system. CNS Drug Rev 7:387–398

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (18300128 to A.N.) and grants from the US National Institutes of Health to G.L.S. (MH067488), J.A.B. (MH79710, MH083711, and DA016672), and P.G. and A.C.N. (MH 090963 and DA10044); the Michael Stern Parkinson's Research Foundation (to P.G.); and the Department of Defense (DOD/USAMRAA W81XWH-09-1-402 and W81XWH-10-1-0640 to P.G.). G.L.S. was supported by funds from Intra-Cellular Therapies Inc. G.L.S. receives additional support from the United States Army Medical Research and Materiel Command NETRP Program (DAMD 17-03-2-0019, W81XWH-05-1-0400, and W81XWH-06-C-0013 to Intra-Cellular Therapies Inc). The authors thank Yukako Terasaki, Keiko Fujisaki, Michiko Sakamoto, Minal Rana, Tiffany Tsui, and Tomonori Furukawa for excellent technical assistance.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan

    Mahomi Kuroiwa, Takahide Shuto & Akinori Nishi

  2. Japan Science of Technology Agency, CREST, Tokyo, 102-0075, Japan

    Mahomi Kuroiwa, Takahide Shuto, Yuchio Yanagawa & Akinori Nishi

  3. Intra-Cellular Therapies, Inc, New York, NY, 10032, USA

    Gretchen L. Snyder

  4. Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 431-3192, Japan

    Atsuo Fukuda

  5. Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan

    Yuchio Yanagawa

  6. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, 75390-9070, USA

    David R. Benavides & James A. Bibb

  7. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06510, USA

    Angus C. Nairn

  8. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, 10021, USA

    Angus C. Nairn, Paul Greengard & Akinori Nishi

Authors
  1. Mahomi Kuroiwa
    View author publications

    Search author on:PubMed Google Scholar

  2. Gretchen L. Snyder
    View author publications

    Search author on:PubMed Google Scholar

  3. Takahide Shuto
    View author publications

    Search author on:PubMed Google Scholar

  4. Atsuo Fukuda
    View author publications

    Search author on:PubMed Google Scholar

  5. Yuchio Yanagawa
    View author publications

    Search author on:PubMed Google Scholar

  6. David R. Benavides
    View author publications

    Search author on:PubMed Google Scholar

  7. Angus C. Nairn
    View author publications

    Search author on:PubMed Google Scholar

  8. James A. Bibb
    View author publications

    Search author on:PubMed Google Scholar

  9. Paul Greengard
    View author publications

    Search author on:PubMed Google Scholar

  10. Akinori Nishi
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Akinori Nishi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

Expression 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 a–c and 10 mm for a inset and d (DOC 5094 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuroiwa, M., Snyder, G.L., Shuto, T. et al. Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology 219, 1065–1079 (2012). https://doi.org/10.1007/s00213-011-2436-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1007/s00213-011-2436-8

Keywords