Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi


  • Daniela V. Rosa
  • Luiz Alexandre V. Magno
  • Bruno R. Souza
  • Marco A. Romano-Silva
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_557


Historical Background

Recent studies using behavioral analysis of animal models suggest that alterations in critical intracellular signaling pathways have an important role in the pathophysiology and treatment of complex neuropsychiatric disorders. The hypothesis is that, if the vast majority of psychiatric medications exert their primary therapeutic actions in the first week of treatment, the therapeutic effects involve transcriptional changes initiated and maintained by critical intracellular signaling pathways.

The dopaminergic neurotransmission system has been the focus of much research throughout the last few decades, including psychiatric and neurological...

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


  1. Abdolahi A, Acosta G, Breslin FJ, Hemby SE, Lynch WJ. Incubation of nicotine seeking is associated with enhanced protein kinase A-regulated signaling of dopamine- and cAMP-regulated phosphoprotein of 32 kDa in the insular cortex. Eur J Neurosci. 2010;31(4):733–41.PubMedCrossRefGoogle Scholar
  2. Albert KA, Hemmings HC, Jr, Adamo AI, et al. Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia. Arch Gen Psychiat. 2002;59(8):705–12.PubMedCrossRefGoogle Scholar
  3. Andersson M, Usiello A, Borgkvist A, et al. Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons. J Neurosci. 2005;25(37):8432–8.PubMedCrossRefGoogle Scholar
  4. Baracskay KL, Haroutunian V, Meador-Woodruff JH. Dopamine receptor signaling molecules are altered in elderly schizophrenic cortex. Synapse. 2006;60(4):271–9.PubMedCrossRefGoogle Scholar
  5. Beuten J, Ma JZ, Lou XY, Payne TJ, Li MD. Association analysis of the protein phosphatase 1 regulatory subunit 1B (PPP1R1B) gene with nicotine dependence in European- and African-American smokers. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(3):285–90.PubMedCrossRefGoogle Scholar
  6. Bonoiu AC, Mahajan SD, Ding H, et al. Nanotechnology approach for drug addiction therapy: gene silencing using delivery of gold nanorod-siRNA nanoplex in dopaminergic neurons. Proc Natl Acad Sci USA. 2009;106(14):5546–50.PubMedCrossRefGoogle Scholar
  7. Cardno AG, Holmans PA, Rees MI, et al. A genomewide linkage study of age at onset in schizophrenia. Am J Med Genet. 2001;105(5):439–45.PubMedCrossRefGoogle Scholar
  8. Cash R, Raisman R, Ploska A, Agid Y. Dopamine D-1 receptor and cyclic AMP-dependent phosphorylation in Parkinson’s disease. J Neurochem. 1987;49(4):1075–83.PubMedCrossRefGoogle Scholar
  9. Chen JC, Chen PC, Chiang YC. Molecular mechanisms of psychostimulant addiction. Chang Gung Med J. 2009;32(2):148–54.PubMedGoogle Scholar
  10. Clinton SM, Ibrahim HM, Frey KA, et al. Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin. Am J Psychiat. 2005;162(10):1859–71.PubMedCrossRefGoogle Scholar
  11. Dick DM, Foroud T, Flury L, et al. Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet. 2003;73(1):107–14.PubMedCrossRefGoogle Scholar
  12. Ehrman LA, Williams MT, Schaefer TL, et al. 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. 2006;5(7):540–51.PubMedCrossRefGoogle Scholar
  13. Feldcamp LA, Souza RP, Romano-Silva M, et al. Reduced prefrontal cortex DARPP-32 mRNA in completed suicide victims with schizophrenia. Schizophr Res. 2008;103(1–3):192–200.PubMedCrossRefGoogle Scholar
  14. Fernandez-Ruiz J, Hernandez M, Ramos JA. Cannabinoid-dopamine interaction in the pathophysiology and treatment of CNS disorders. CNS Neurosci Ther. 2010;16(3):e72–91.PubMedCrossRefGoogle Scholar
  15. Fienberg AA, Greengard P. The DARPP-32 knockout mouse. Brain Res Brain Res Rev. 2000;31(2–3):313–9.PubMedCrossRefGoogle Scholar
  16. Fienberg AA, Hiroi N, Mermelstein PG, et al. DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. Science. 1998;281(5378):838–42.PubMedCrossRefGoogle Scholar
  17. Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE. Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. Proc Natl Acad Sci USA. 2007;104(41):16311–6.PubMedCrossRefGoogle Scholar
  18. Goodman A. Neurobiology of addiction. An integrative review. Biochem Pharmacol. 2008;75(1):266–322.PubMedCrossRefGoogle Scholar
  19. Girault JA, Hemmings HC, et al. Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II. J Biol Chem. 1989;264(36):21748–59.PubMedGoogle Scholar
  20. Heyser CJ, Fienberg AA, Greengard P, Gold LH. DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task. Brain Res. 2000;867(1–2):122–30.PubMedCrossRefGoogle Scholar
  21. Ishikawa M, Mizukami K, Iwakiri M, Asada T. Immunohistochemical and immunoblot analysis of Dopamine and cyclic AMP-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32) in the prefrontal cortex of subjects with schizophrenia and bipolar disorder. Prog Neuropsychopharmacol Biol Psychiat. 2007;31(6):1177–81.CrossRefGoogle Scholar
  22. Lindskog M, Svenningsson P, Pozzi L, et al. Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Nature. 2002;418(6899):774–8.PubMedCrossRefGoogle Scholar
  23. Mahajan SD, Aalinkeel R, Reynolds JL, et al. Therapeutic targeting of “DARPP-32”: a key signaling molecule in the dopiminergic pathway for the treatment of opiate addiction. Int Rev Neurobiol. 2009;88:199–222.PubMedCrossRefGoogle Scholar
  24. Meyer-Lindenberg A, Straub RE, Lipska BK, et al. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest. 2007;117(3):672–82.PubMedCrossRefGoogle Scholar
  25. Reis HJ, Rosa DV, Guimaraes MM, et al. Is DARPP-32 a potential therapeutic target? Expert Opin Ther Targets. 2007;11(12):1649–61.PubMedCrossRefGoogle Scholar
  26. Risinger FO, Freeman PA, Greengard P, Fienberg AA. Motivational effects of ethanol in DARPP-32 knock-out mice. J Neurosci. 2001;21(1):340–8.PubMedGoogle Scholar
  27. Rosa DV, Souza RP, Souza BR, et al. DARPP-32 expression in rat brain after electroconvulsive stimulation. Brain Res. 2007;1179:35–41.PubMedCrossRefGoogle Scholar
  28. Souza BR, Motta BS, Rosa DV, et al. DARPP-32 and NCS-1 expression is not altered in brains of rats treated with typical or atypical antipsychotics. Neurochem Res. 2008;33(3):533–8.PubMedCrossRefGoogle Scholar
  29. Souza RP, Soares EC, Rosa DV, et al. Cerebral DARPP-32 expression after methylphenidate administration in young and adult rats. Int J Dev Neurosci. 2009;27(1):1–7.PubMedCrossRefGoogle Scholar
  30. Souza BR, Torres KC, Miranda DM, et al. Lack of effects of typical and atypical antipsychotics in DARPP-32 and NCS-1 levels in PC12 cells overexpressing NCS-1. J Negat Results Biomed. 2010;9:4.PubMedCrossRefGoogle Scholar
  31. Svenningsson P, Fienberg AA, Allen PB, et al. Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32. J Neurochem. 2000;75(1):248–57.PubMedCrossRefGoogle Scholar
  32. Svenningsson P, Nairn AC, Greengard P. DARPP-32 mediates the actions of multiple drugs of abuse. AAPS J. 2005;7(2):E353–60.PubMedCrossRefGoogle Scholar
  33. Svenningsson P, Nishi A, Fisone G, et al. DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol. 2004;44:269–96.PubMedCrossRefGoogle Scholar
  34. Svenningsson P, Tzavara ET, Carruthers R, et al. Diverse psychotomimetics act through a common signaling pathway. Science. 2003;302(5649):1412–5.PubMedCrossRefGoogle Scholar
  35. Svenningsson P, Tzavara ET, Witkin JM, et al. Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). Proc Natl Acad Sci USA. 2002;99(5):3182–7.PubMedCrossRefGoogle Scholar
  36. Torres KC, Souza BR, Miranda DM, et al. The leukocytes expressing DARPP-32 are reduced in patients with schizophrenia and bipolar disorder. Prog Neuropsychopharmacol Biol Psychiat. 2009;33(2):214–9.CrossRefGoogle Scholar
  37. West AR, Grace AA. Opposite influences of endogenous dopamine D1 and D2 receptor activation on activity states and electrophysiological properties of striatal neurons: studies combining in vivo intracellular recordings and reverse microdialysis. J Neurosci. 2002;22(1):294–304.PubMedGoogle Scholar
  38. Zachariou V, OitMarand M, Allen PB, et al. Reduction of cocaine place preference in mice lacking the protein phosphatase 1 inhibitors DARPP 32 or Inhibitor 1. Biol Psychiatry. 2002;51(8):612–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Daniela V. Rosa
    • 1
  • Luiz Alexandre V. Magno
    • 1
  • Bruno R. Souza
    • 2
  • Marco A. Romano-Silva
    • 3
  1. 1.INCT de Medicina MolecularUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Department of Cell & Systems Biology, Centre for the Analysis of Genome Evolution and FunctionUniversity of TorontoTorontoCanada
  3. 3.INCT de Medicina Molecular; Departamento de Saúde MentalUniversidade Federal de Minas GeraisBelo HorizonteBrazil