Skip to main content

Advertisement

SpringerLink
Log in

DARPP-32 mediates the actions of multiple drugs of abuse

  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Drugs of abuse share the ability to enhance dopaminergic neurotransmission in the dorsal and ventral striatum. The action of dopamine is modulated by additional neurotransmitters, including glutamate, serotonin and adenosine. All these neurotransmitters regulate the phosphorylation state of Dopaminal serine/threonine protein phosphatase, PP-1. Phosphorylatine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32). Phosphorylation at Thr34 by protein kinase A converts DARPP-32 into a potent inhibitor of the multifunctioon at Thr75 by Cdk5 converts DARPP-32 into an inhibitor of protein kinase A. The state of phosphorylation of DARPP-32 at Thr34 also depends on the phosphorylation state of Ser97 and Ser130, which are phosphorylated by CK2 and CK1, respectively. By virtue of regulation of these 4 phosphorylation sites, and through its ability to modulate the activity of PP-1 and protein kinase A, DARPP-32 plays a key role in integrating a variety of biochemical, electrophysiological, and behavioral responses controlled by dopamine and other neurotransmitters. Importantly, there is now alarge body of evidence that supports a key role for DARPP-32-dependent signaling in mediating the actions of multiple drugs of abuse including cocaine, amphetamine, nicotine, caffeine, LSD, PCP, ethanol and morphine.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Walaas SI, Aswad DW, Greengard P. A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions.Nature. 1983;301:69–71.

    Article  PubMed  CAS  Google Scholar 

  2. Hemmings HC Jr, Greengard P, Tung HY, Cohen P. DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1.Nature. Aug 9–15, 1984;310(5977):503–505.

    Article  PubMed  CAS  Google Scholar 

  3. Ouimet CC, Langley-Gullion KC, Greengard P. Quantitative immunocytochemistry of DARPP-32-expressing neurons in the rat caudatoputamen.Brain Res. 1998;808:8–12.

    Article  PubMed  CAS  Google Scholar 

  4. da Cruz e Silva EF, Fox CA, Ouimet CC, Gustafson E, Watson SJ, Greengard P. Differential expression of protein phosphatase 1 isoforms in mammalian brain.J Neurosci. 1995;15:3375–3389.

    PubMed  Google Scholar 

  5. Girault JA Jr, Hemmings HC Jr, Williams KR, Nairn AC, Greengard P. Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II.J Biol Chem. 1989;264:21748–21759.

    PubMed  CAS  Google Scholar 

  6. Desouits F, Cohen D, Nairn AC, Greengard P, Girault JA. Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase I in vitro and in vivo.J Biol Chem. 1995;270:8772–8778.

    Article  Google Scholar 

  7. Desdouits F, Siciliano JC, Greengard P, Girault JA. Dopamine- and cAMP-regulated phosphoprotein DARPP-32: phosphorylation of Ser-137 by casein kinase I inhibits dephosphorylation of Thr-34 by calcineurin.Proc Natl Acad Sci USA. 1995;92:2682–2685.

    Article  PubMed  CAS  Google Scholar 

  8. Bibb JA, Snyder GL, Nishi A, et al. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons.Nature. 1999;402:669–671.

    Article  PubMed  CAS  Google Scholar 

  9. Ouimet CC, Jr, Miller PE Jr, Hemmings HC Jr, Walaas SI, Greengard P. DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III Immunocytochemical localization.J Neurosci. 1984;4:111–124.

    PubMed  CAS  Google Scholar 

  10. Yoshida M, Precht W. Monosynaptic inhibition of neurons of the substantia nigra by caudato-nigral fibers.Brain Res. 1971;32:225–228.

    Article  PubMed  CAS  Google Scholar 

  11. Beckstead RM, Cruz CJ. Striatal axons to the globus pallidus, entopeduncular nucleus and substantia nigra come mainly from separate cell populations in cat.Neuroscience. 1986;19:147–158.

    Article  PubMed  CAS  Google Scholar 

  12. Gerfen CR 3rd, Young WS 3rd. Distribution of striatonigral and striatopallidal peptidergic neurons in both patch and matrix compartments: an in situ hybridization histochemistry and fluorescent retrograde tracing study.Brain Res. 1988;460:161–167.

    Article  PubMed  CAS  Google Scholar 

  13. Kawaguchi Y, Wilson CJ, Emson PC. Projection subtypes of rat neostriatal matrix cells revealed by intracellular injection of biocytin.J Neurosci. 1990;10:3421–3438.

    PubMed  CAS  Google Scholar 

  14. Anderson KD, Reiner A. Immunohistochemical localization of DARPP-32 in striatal projection neurons and striatal interneurons: implications for the localization of D1-like dopamine receptors on different types of striatal neurons.Brain Res. 1991;568:235–243.

    Article  PubMed  CAS  Google Scholar 

  15. Ouimet CC, Greengard P. Distribution of DARPP-32 in the basal ganglia: an electron microscopic study.J Neurocytol. 1990;19:39–52.

    Article  PubMed  CAS  Google Scholar 

  16. Carboni E, Imperato A, Perezzani L, Di Chiara G. Amphetamine, cocaine, phencyclidine and nomifensive increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats.Neuroscience. 1989;28:653–661.

    Article  PubMed  CAS  Google Scholar 

  17. Parsons LH, Koob GF, Weiss F. Serotonin dysfunction in the nucleus accumbens of rats during withdrawal after unlimited access to intravenous cocaine.J Pharmacol Exp Ther. 1995;274:1182–1191.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Stoof JC, Kebabian JW. Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum.Nature. 1981;294:366–368.

    Article  PubMed  CAS  Google Scholar 

  20. Bergson C, Levenson R, Goldman-Rakic PS, Lidow MS. Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling.Trends Pharmacol Sci. 2003;24:486–492.

    Article  PubMed  CAS  Google Scholar 

  21. Nishi A, Snyder GL, Greengard P. Bidirectional regulation of DARPP-32 phosphorylation by dopamine.J Neurosci. 1997;17:8147–8155.

    PubMed  CAS  Google Scholar 

  22. Gerfen CR, Engber TM, Mahan LC, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons.Science. 1990;250:1429–1432.

    Article  PubMed  CAS  Google Scholar 

  23. Surmeier DJ, Song WJ, Yan Z. Coordinated expression of dopamine receptors in neostriatal medium spiny neurons.J Neurosci. 1996;16:6579–6591.

    PubMed  CAS  Google Scholar 

  24. Aizman O, Brismar H, Uhlen P, et al. Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons.Nat Neurosci. 2000;3:226–230.

    Article  PubMed  CAS  Google Scholar 

  25. Svenningsson P, Lindskog M, Ledent C, et al. Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors.Proc Natl Acad Sci USA. 2000;97:1856–1860.

    Article  PubMed  CAS  Google Scholar 

  26. Lindskog M, Svenningsson P, Fredholm BB, Greengard P, Fisone G. Activation of dopamine D2 receptors decreases DARPP-32 phosphorylation in striatonigral and striatopallidal projection neurons via different mechanisms.Neuroscience. 1999;88:1005–1008.

    Article  PubMed  CAS  Google Scholar 

  27. Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P. Amplification of dopaminergic signaling by a positive feedback loop.Proc Natl Acad Sci USA. 2000;97:12840–12845.

    Article  PubMed  CAS  Google Scholar 

  28. Halpain S, Girault JA, Greengard P. Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices.Nature. 1990;343:369–372.

    Article  PubMed  CAS  Google Scholar 

  29. Nishi A, Bibb JA, Matsuyama S, et al. Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-sites by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A.J Neurochem. 2002;81:832–841.

    Article  PubMed  CAS  Google Scholar 

  30. Schoepp DD, Jane DE, Monn JA. Pharmacological agents acting at subtypes of metabotropic glutamate receptors.Neuropharmacology. 1999;38:1431–1476.

    Article  PubMed  CAS  Google Scholar 

  31. Tallaksen-Greene SJ, Kaatz KW, Romano C, Albin RL. Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons.Brain Res. 1998;780:210–217.

    Article  PubMed  CAS  Google Scholar 

  32. Testa CM, Friberg IK, Weiss SW, Standaert DG. Immunohistochemical localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the rat basal ganglia.J Comp Neurol. 1998;390:5–19.

    Article  PubMed  CAS  Google Scholar 

  33. Nishi A, Liu F, Matsuyama S, et al. Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling.Proc Natl Acad Sci USA. 2003;100:1322–1327.

    Article  PubMed  Google Scholar 

  34. Liu F, Ma XH, Ule J, et al. Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors.Proc Natl Acad Sci USA. 2001;98:11062–11068.

    Article  PubMed  CAS  Google Scholar 

  35. Liu F, Virshup DM, Nairn AC, Greengard P. Mechanism of regulation of casein kinase I activity by group I metabotropic glutamate receptors.J Biol Chem. 2002;277:45393–45399.

    Article  PubMed  CAS  Google Scholar 

  36. Nishi A, Watanabe Y, Higashi H, Tanaka M, Nairn AC, Greengard P. Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades.Proc Natl Acad Sci USA. 2005;102:1199–1204.

    Article  PubMed  CAS  Google Scholar 

  37. Barnes NM, Sharp T. A review of central 5-HT receptors and their function.Neuropharmacology. 1999;38:1083–1152.

    Article  PubMed  CAS  Google Scholar 

  38. Svenningsson P, Tzavara ET, Liu F, Fienberg AA, Nomikos GG, Greengard P. DARPP-32 mediates serotonergic neurotransmission in the forebrain.Proc Natl Acad Sci USA. 2002;99:3188–3193.

    Article  PubMed  CAS  Google Scholar 

  39. Schiffmann SN, Jacobs O, Vanderhaeghen JJ. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study.J Neurochem. 1991;57:1062–1067.

    Article  PubMed  CAS  Google Scholar 

  40. Svenningsson P, Lindskog M, Rognoni F, Fredholm BB, Greengard P, Fisone G. Activation of adenosine A2A and dopamine D1 receptors stimulates cyclic AMP-dependent phosphorylation of DARPP-32 in distinct populations of striatal projection neurons.Neuroscience. 1998;84:223–228.

    Article  PubMed  CAS  Google Scholar 

  41. Lindskog M, Svenningsson P, Pozzi L, et al. Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine.Nature. 2002;418:774–778.

    Article  PubMed  CAS  Google Scholar 

  42. Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence.Nat Rev Neurosci. 2001;2:695–703.

    Article  PubMed  CAS  Google Scholar 

  43. Nestler EJ. Molecular basis of long-term plasticity underlying addiction.Nat Rev Neurosci. 2001;2:119–128.

    Article  PubMed  CAS  Google Scholar 

  44. Fienberg AA, Hiroi N, Mermelstein PG, et al. DARPP-32: regulator of the efficacy of dopaminergic neurotransmission.Science. 1998;281:838–842.

    Article  PubMed  CAS  Google Scholar 

  45. Svenningsson P, Tzavara ET, Carruthers R, et al. Diverse psychotomimetics act through a common on signaling pathway.Science. 2003;302:1412–1415.

    Article  PubMed  CAS  Google Scholar 

  46. Fienberg AA, Greengard P. The DARPP-32 knockout mouse.Brain Res Brain Res Rev. 2000;31:313–319.

    Article  PubMed  CAS  Google Scholar 

  47. Nairn AC, Svenningsson P, Nishi A, Fisone G, Girault JA, Greengard P. The role of DARPP-32 in the actions of drugs of abuse.Neuropharmacology 2004;47:14–23.

    Article  PubMed  CAS  Google Scholar 

  48. Valjent E, Pascoli V, Svenningsson P, et al. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum.Proc Natl Acad Sci USA. 2005;102:491–496.

    Article  PubMed  CAS  Google Scholar 

  49. Bibb JA, Chen J, Taylor JR, et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5.Nature. 2001;410:376–380.

    Article  PubMed  CAS  Google Scholar 

  50. Liu FC, Graybiel AM. Spatiotemporal dynamics of CREB phosphorylation: transient versus sustained phosphorylation in the developing striatum.Neuron. 1996;17:1133–1144.

    Article  PubMed  CAS  Google Scholar 

  51. Hagiwara M, Alberts A, Brindle P, et al. Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB.Cell. 1992;70:105–113.

    Article  PubMed  CAS  Google Scholar 

  52. Yan Z, Feng J, Fienberg AA, Greengard P. D(2) dopamine receptors induce mitogen-activated protein kinase and cAMP response element-binding protein phosphorylation in neurons.Proc Natl Acad Sci USA. 1999;96:11607–11612.

    Article  PubMed  CAS  Google Scholar 

  53. Svenningsson P, Fienberg AA, Allen PB, et al. Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32.J Neurochem. 2000;75:248–257.

    Article  PubMed  CAS  Google Scholar 

  54. Hiroi N, Fienberg AA, Haile CN, et al. Neuronal and behavioral abnormalities in striatal function in DARPP-32-mutant mice.Eur J Neurosci. 1999;11:1114–1118.

    Article  PubMed  CAS  Google Scholar 

  55. Zachariou V, Benoit-Marand M, Allen PB, et al. Reduction of cocaine place preference in mice lacking the protein phosphatase 1 inhibitors DARPP32 or Inhibitor 1.Biol Psychiatry. 2002;51:612–620.

    Article  PubMed  CAS  Google Scholar 

  56. Heyser CJ, Fienberg AA, Greengard P, Gold LH. DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task.Brain Res. 2000;867:122–130.

    Article  PubMed  CAS  Google Scholar 

  57. Schoffelmeer AN, Hansen HA, Stoof JC, Mulder AH. Blockade of D-2 dopamine receptors trongly enhances the potency of enkephalins to inhibit dopamine-sensitive adenylate cyclase in rat neostriatum: involvement of delta- and mu-opioid receptors.J Neurosci. 1986;6:2235–2239.

    PubMed  CAS  Google Scholar 

  58. Georges F, Stinus L, Bloch B, Le Moine C. Chronic morphine exposure and spontaneous withdrawal are associated with modifications of dopamine receptor and neuropeptide gene expression in the rat striatum.Eur J Neurosci. 1999;11:481–490.

    Article  PubMed  CAS  Google Scholar 

  59. Lindskog M, Svenningsson P, Fredholm B, Greengard P, Fisone G. Mu- and delta-opioid receptor agonists inhibit DARPP-32 phosphorylation in distinct populations of striatal projection neurons.Eur J Neurosci. 1999;11:2182–2186.

    Article  PubMed  CAS  Google Scholar 

  60. Role LW, Berg DK. Nicotinic receptors in the development and modulation of CNS synapses.Neuron. 1996;16:1077–1085.

    Article  PubMed  CAS  Google Scholar 

  61. Wonnacott S. Presynaptic nicotinic ACh receptors.Trends Neurosci. 1997;20:92–98.

    Article  PubMed  CAS  Google Scholar 

  62. Ramirez-Latorre J, Crabtree G, Turner J, Role L. Molecular composition and biophysical characteristics of nicotinic receptors. In: Arneric SP, Brioni JD, eds.Neuronal nicotinic receptors: pharmacology and therapeutic opportunities. New York: Wiley-Liss, Inc, 1999:43–64.

    Google Scholar 

  63. Zoli M, Moretti M, Zanardi A, McIntosh JM, Clementi F, Gotti C. Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum.J Neurosci. 2002;22:8785–8789.

    PubMed  CAS  Google Scholar 

  64. Nomikos GG, Schilstrom B, Hildebrand BE, Panagis G, Grenhoff J, Svensson TH. Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness.Behav Brain Res. 2000;113:97–103.

    Article  PubMed  CAS  Google Scholar 

  65. Hamada M, Higashi H, Nairn AC, Greengard P, Nishi A. Differential regulation of dopamine D1 and D2 signaling by nicotine in neostriatal neurons.J Neurochem. 2004;90:1094–1103.

    Article  PubMed  CAS  Google Scholar 

  66. Aghajanian GK, Marek GJ. Serotonin and hallucinogens.Neuropsychopharmacology. 1999;21:16S-23S.

    PubMed  CAS  Google Scholar 

  67. Grailhe R, Waeber C, Dulawa SC, et al. Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor.Neuron. 1999;22:581–591.

    Article  PubMed  CAS  Google Scholar 

  68. Glennon RA, Titeler M, McKenney JD. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents.Life Sci. 1984;35:2505–2511.

    Article  PubMed  CAS  Google Scholar 

  69. Sawa A, Snyder SH. Schizophrenia: diverse approaches to a complex disease.Science. 2002;296:692–695.

    Article  PubMed  CAS  Google Scholar 

  70. Carlezon WA Jr, Wise RA. Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex.J Neurosci. 1996;16:3112–3122.

    PubMed  CAS  Google Scholar 

  71. Druhan JP, Rajabi H, Stewart J. MK-801 increases locomotor activity without elevating extracellular dopamine levels in the nucleus accumbens.Synapse. 1996;24:135–146.

    Article  PubMed  CAS  Google Scholar 

  72. Pierce RC, Meil WM, Kalivas PW. The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission.Psychopharmacology (Berl). 1997;133:188–195.

    Article  CAS  Google Scholar 

  73. Svenningsson P, Le Moine C, Fisone G, Fredholm BB. Distribution, biochemistry and function of striatal adenosine A2A receptors.Prog Neurobiol. 1999;59:355–396.

    Article  PubMed  CAS  Google Scholar 

  74. Ledent C, Vaugeois JM, Schiffmann SN, et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.Nature. 1997;388:674–678.

    Article  PubMed  CAS  Google Scholar 

  75. Risinger FO, Freeman PA, Greengard P, Fienberg AA. Motivational effects of ethanol in DARPP-32 knock-out mice.J Neurosci. 2001;21:340–348.

    PubMed  CAS  Google Scholar 

  76. Maldve RE, Zhang TA, Ferrani-Kile K, et al. DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens.Nat Neurosci. 2002;5:641–648.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Per Svenningsson, Angus C. Nairn & Paul Greengard

  2. Department of Psychiatry, Yale University School of Medicine, 06508, New Haven, CT

    Angus C. Nairn

Authors
  1. Per Svenningsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angus C. Nairn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Greengard
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Published: October 5, 2005

Rights and permissions

Reprints and permissions

About this article

Cite this article

Svenningsson, P., Nairn, A.C. & Greengard, P. DARPP-32 mediates the actions of multiple drugs of abuse. AAPS J 7, 35 (2005). https://doi.org/10.1208/aapsj070235

Download citation

  • Received:

  • Accepted:

  • DOI: https://doi.org/10.1208/aapsj070235

Keywords

Search

Navigation