Home LiteratureArticle Details
PMID: 20720111 Published · ppublish English Journal Article

Role of aberrant striatal dopamine D1 receptor/cAMP/protein kinase A/DARPP32 signaling in the paradoxical calming effect of amphetamine.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 30 ·No. 33 ·2010-08-18 ·Pages 11043-56

Napolitano F, Bonito-Oliva A, Federici M, Carta M, Errico F, Magara S, Martella G, Nisticò R, Centonze D, Pisani A, Gu HH, Mercuri NB, Usiello A

Abstract

Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D(2) receptor (D(2)R) function. However, although we demonstrated that striatal D(1) receptor (D(1)R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D(2)R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D(1)R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.

MeSH Terms
Amphetamine/pharmacology Animals Central Nervous System Stimulants/pharmacology Corpus Striatum/drug effects,physiology Cyclic AMP/metabolism Cyclic AMP-Dependent Protein Kinases/metabolism Discrimination, Psychological/drug effects,physiology Dopamine/metabolism Dopamine Plasma Membrane Transport Proteins/genetics Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism Gene Knock-In Techniques Long-Term Potentiation/drug effects,physiology Male Mice Mice, Transgenic Motor Activity/drug effects,physiology Mutation Random Allocation Receptors, Dopamine D1/metabolism Receptors, Dopamine D2/metabolism Signal Transduction
Chemicals
Central Nervous System Stimulants Dopamine Plasma Membrane Transport Proteins Dopamine and cAMP-Regulated Phosphoprotein 32 Ppp1r1b protein, mouse Receptors, Dopamine D1 Receptors, Dopamine D2 Amphetamine Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dopamine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Napolitano Francesco
Centro Ingegneria Genetica Biotecnologie Avanzate, 80131 Naples, Italy.
Bonito-Oliva Alessandra
Federici Mauro
Carta Manolo
Errico Francesco
Magara Salvatore
Martella Giuseppina
Nisticò Robert
Centonze Diego
Pisani Antonio
Gu Howard H
Mercuri Nicola B
Usiello Alessandro
References (77)
77 references, click to expand
  1. Functional hyperdopaminergia in dopamine transporter knock-out mice.
    Biol Psychiatry. 1999 Aug 1;46(3):303-11 PMID: 10435196
  2. Loss of autoreceptor functions in mice lacking the dopamine transporter.
    Nat Neurosci. 1999 Jul;2(7):649-55 PMID: 10404198
  3. Properties of the hyperpolarization-activated cation current Ih in rat midbrain dopaminergic neurons.
    Eur J Neurosci. 1995 Mar 1;7(3):462-9 PMID: 7773443
  4. Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study.
    Biol Psychiatry. 2005 Apr 1;57(7):793-801 PMID: 15820237
  5. The effects of methylphenidate on knockin mice with a methylphenidate-resistant dopamine transporter.
    J Pharmacol Exp Ther. 2008 Nov;327(2):554-60 PMID: 18698001
  6. DARPP-32: an integrator of neurotransmission.
    Annu Rev Pharmacol Toxicol. 2004;44:269-96 PMID: 14744247
  7. Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity.
    J Neurosci. 2003 Sep 17;23(24):8506-12 PMID: 13679419
  8. Paradoxical striatal cellular signaling responses to psychostimulants in hyperactive mice.
    J Biol Chem. 2006 Oct 27;281(43):32072-80 PMID: 16954211
  9. Vitamin A deficiency induces motor impairments and striatal cholinergic dysfunction in rats.
    Neuroscience. 2006;139(4):1163-72 PMID: 16530976
  10. Pharmacologic treatment of attention deficit hyperactivity disorder.
    Psychiatr Clin North Am. 1992 Mar;15(1):1-27 PMID: 1347936
  11. Nomifensine maleate in adult attention deficit disorder.
    J Nerv Ment Dis. 1989 May;177(5):296-9 PMID: 2651559
  12. Distinct functions of the two isoforms of dopamine D2 receptors.
    Nature. 2000 Nov 9;408(6809):199-203 PMID: 11089973
  13. Neurotransmitter transporters as molecular targets for addictive drugs.
    Drug Alcohol Depend. 1998 Jun-Jul;51(1-2):87-96 PMID: 9716932
  14. Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors.
    J Neurochem. 2006 Jan;96(2):482-8 PMID: 16336634
  15. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration.
    Behav Brain Res. 1998 Jul;94(1):127-52 PMID: 9708845
  16. Reprint of "Neurobiology of animal models of attention-deficit hyperactivity disorder".
    J Neurosci Methods. 2007 Nov 30;166(2):I-XIV PMID: 17980763
  17. DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1.
    Nature. 1984 Aug 9-15;310(5977):503-5 PMID: 6087160
  18. Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia.
    Sci Signal. 2009 Jul 21;2(80):ra36 PMID: 19622833
  19. The GTP-binding protein Rhes modulates dopamine signalling in striatal medium spiny neurons.
    Mol Cell Neurosci. 2008 Feb;37(2):335-45 PMID: 18035555
  20. Getting specialized: presynaptic and postsynaptic dopamine D2 receptors.
    Curr Opin Pharmacol. 2009 Feb;9(1):53-8 PMID: 19138563
  21. Brain dopamine transporter levels in treatment and drug naïve adults with ADHD.
    Neuroimage. 2007 Feb 1;34(3):1182-90 PMID: 17126039
  22. Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine.
    Nature. 2002 Aug 15;418(6899):774-8 PMID: 12181566
  23. Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder.
    Lancet. 2003 Nov 22;362(9397):1699-707 PMID: 14643117
  24. Diverse psychotomimetics act through a common signaling pathway.
    Science. 2003 Nov 21;302(5649):1412-5 PMID: 14631045
  25. Distribution, biochemistry and function of striatal adenosine A2A receptors.
    Prog Neurobiol. 1999 Nov;59(4):355-96 PMID: 10501634
  26. Genetics of adult attention-deficit/hyperactivity disorder.
    Psychiatr Clin North Am. 2004 Jun;27(2):303-21 PMID: 15063999
  27. Amphetamine distorts stimulation-dependent dopamine overflow: effects on D2 autoreceptors, transporters, and synaptic vesicle stores.
    J Neurosci. 2001 Aug 15;21(16):5916-24 PMID: 11487614
  28. Dopamine transporter inhibition is required for cocaine-induced stereotypy.
    Neuroreport. 2008 Jul 16;19(11):1137-40 PMID: 18596615
  29. The genetics of attention deficit hyperactivity disorder.
    Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R275-82 PMID: 16244326
  30. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons.
    Nature. 1999 Dec 9;402(6762):669-71 PMID: 10604473
  31. Response times of carbon fiber microelectrodes to dynamic changes in catecholamine concentration.
    Anal Chem. 2002 Feb 1;74(3):539-46 PMID: 11838672
  32. Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia.
    Neuropsychopharmacology. 2007 Oct;32(10):2108-16 PMID: 17342172
  33. Attention-deficit/hyperactivity disorder: a selective overview.
    Biol Psychiatry. 2005 Jun 1;57(11):1215-20 PMID: 15949990
  34. High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.
    Am J Psychiatry. 1999 Aug;156(8):1209-15 PMID: 10450262
  35. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.
    Science. 1999 Jan 15;283(5400):397-401 PMID: 9888856
  36. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis.
    Neuropsychol Rev. 2007 Mar;17(1):39-59 PMID: 17318414
  37. Amplification of dopaminergic signaling by a positive feedback loop.
    Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12840-5 PMID: 11050161
  38. Dopamine receptors: molecular biology, biochemistry and behavioural aspects.
    Pharmacol Ther. 1994;64(2):291-370 PMID: 7878079
  39. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum.
    J Neurosci. 2001 Jun 15;21(12):4390-9 PMID: 11404425
  40. The binding sites for cocaine and dopamine in the dopamine transporter overlap.
    Nat Neurosci. 2008 Jul;11(7):780-9 PMID: 18568020
  41. Distribution of adenosine A2 receptor mRNA in the human brain.
    Neurosci Lett. 1991 Sep 16;130(2):177-81 PMID: 1795877
  42. Profound neuronal plasticity in response to inactivation of the dopamine transporter.
    Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4029-34 PMID: 9520487
  43. Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum.
    Brain Res Mol Brain Res. 1992 Jul;14(3):186-95 PMID: 1279342
  44. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'.
    Nat Protoc. 2006;1(3):1306-11 PMID: 17406415
  45. Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons.
    J Neurochem. 1999 May;72(5):2015-21 PMID: 10217279
  46. Blockade of M2-like muscarinic receptors enhances long-term potentiation at corticostriatal synapses.
    Eur J Neurosci. 1998 Sep;10(9):3020-3 PMID: 9758172
  47. Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder.
    Neuropsychopharmacology. 1996 Feb;14(2):125-37 PMID: 8822535
  48. The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents.
    Neurosci Biobehav Rev. 2007;31(5):673-704 PMID: 17368764
  49. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter.
    Nature. 1996 Feb 15;379(6566):606-12 PMID: 8628395
  50. G(olf)alpha mediates dopamine D1 receptor signaling.
    J Neurosci. 2000 Aug 15;20(16):RC91 PMID: 10924528
  51. 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 U S A. 2000 Feb 15;97(4):1856-60 PMID: 10677546
  52. Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4305-9 PMID: 12651945
  53. Dopamine phenotype and behaviour in animal models: in relation to attention deficit hyperactivity disorder.
    Neurosci Biobehav Rev. 2003 Nov;27(7):623-37 PMID: 14624807
  54. A pincer-like configuration of TM2 in the human dopamine transporter is responsible for indirect effects on cocaine binding.
    Neuropharmacology. 2005 Nov;49(6):780-90 PMID: 16216288
  55. Mechanism of action of agents used in attention-deficit/hyperactivity disorder.
    J Clin Psychiatry. 2006;67 Suppl 8:32-8 PMID: 16961428
  56. Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation, opposing forms of synaptic plasticity.
    J Neurosci. 2000 Nov 15;20(22):8443-51 PMID: 11069952
  57. Candidate gene studies of ADHD: a meta-analytic review.
    Hum Genet. 2009 Jul;126(1):51-90 PMID: 19506906
  58. Loss of autoreceptor function in dopaminergic neurons from dopamine D2 receptor deficient mice.
    Neuroscience. 1997 Jul;79(2):323-7 PMID: 9200717
  59. The nature and causes of hippocampal long-term potentiation.
    Prog Brain Res. 1990;83:233-50 PMID: 2168058
  60. Functional neuroimaging of attention-deficit/hyperactivity disorder: a review and suggested future directions.
    Biol Psychiatry. 2005 Jun 1;57(11):1273-84 PMID: 15949999
  61. Regulation of phosphorylation of the GluR1 AMPA receptor in the neostriatum by dopamine and psychostimulants in vivo.
    J Neurosci. 2000 Jun 15;20(12):4480-8 PMID: 10844017
  62. Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro.
    J Neurosci. 1989 Oct;9(10):3463-81 PMID: 2795134
  63. The neostriatal mosaic: multiple levels of compartmental organization.
    Trends Neurosci. 1992 Apr;15(4):133-9 PMID: 1374971
  64. Dopamine transporter mutant mice in experimental neuropharmacology.
    Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):301-13 PMID: 18057916
  65. In vivo comparison of the regulation of releasable dopamine in the caudate nucleus and the nucleus accumbens of the rat brain.
    J Neurosci. 1986 Apr;6(4):974-82 PMID: 3486259
  66. Association of norepinephrine transporter gene with methylphenidate response.
    J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1154-8 PMID: 15322419
  67. Evoked extracellular dopamine in vivo in the medial prefrontal cortex.
    J Neurochem. 1993 Aug;61(2):637-47 PMID: 8336146
  68. A triple mutation in the second transmembrane domain of mouse dopamine transporter markedly decreases sensitivity to cocaine and methylphenidate.
    J Neurochem. 2005 Jul;94(2):352-9 PMID: 15998286
  69. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs.
    BMC Pharmacol. 2006 Mar 03;6:6 PMID: 16515684
  70. Regulation of striatal tyrosine hydroxylase phosphorylation by acute and chronic haloperidol.
    Eur J Neurosci. 2004 Aug;20(4):1108-12 PMID: 15305880
  71. Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter.
    Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9333-8 PMID: 16754872
  72. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit.
    Neuron. 1996 Jun;16(6):1179-88 PMID: 8663994
  73. Characterization of amperometry for in vivo measurement of dopamine dynamics in the rat brain.
    Talanta. 1994 Jun;41(6):865-74 PMID: 18966011
  74. Dopamine acts on D2 receptors to increase potassium conductance in neurones of the rat substantia nigra zona compacta.
    J Physiol. 1987 Nov;392:397-416 PMID: 2451725
  75. Persistent increase of D-aspartate in D-aspartate oxidase mutant mice induces a precocious hippocampal age-dependent synaptic plasticity and spatial memory decay.
    Neurobiol Aging. 2011 Nov;32(11):2061-74 PMID: 20031274
  76. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine.
    Brain. 2009 Sep;132(Pt 9):2336-49 PMID: 19641103
  77. Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors.
    J Neurosci. 2002 Apr 15;22(8):3293-301 PMID: 11943831
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1682-10.2010
Published
2010-08-18
Pages
11043-56
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6633484
Subset
IM
Grants
NIDA NIH HHS · R01 DA014610 · United States
NIDA NIH HHS · R01 DA020124 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1682-10.2010 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2