Neurochemical Research

, Volume 32, Issue 2, pp 229–240 | Cite as

Dopamine Reduction of GABA Currents in Striatal Medium-sized Spiny Neurons is Mediated Principally by the D1 Receptor Subtype

  • Elizabeth Hernández-Echeagaray
  • Carlos Cepeda
  • Marjorie A. Ariano
  • Mary Kay Lobo
  • David R. Sibley
  • Michael S. LevineEmail author
Original Paper


Dopamine modulates voltage- and ligand-gated currents in striatal medium-sized neurons (MSNs) through the activation of D1- and D2-like family receptors. GABAA receptor-mediated currents are reduced by D1 receptor agonists, but the relative contribution of D1 or D5 receptors in this attenuation has been elusive due to the lack of selective pharmacological agents. Here we examined GABAA receptor-mediated currents and the effects of D1 agonists on MSNs from wildtype and D1 or D5 receptor knockout (KO) mice. Immunohistochemical and single-cell RT-PCR studies demonstrated a lack of compensatory effects after genetic deletion of D1 or D5 receptors. However, the expression of GABAA receptor α1 subunits was reduced in D5 KO mice. At the functional level, whole-cell patch clamp recordings in dissociated MSNs showed that GABA peak current amplitudes were smaller in cells from D5 KO mice indicating that lack of this receptor subtype directly affected GABAA-mediated currents. In striatal slices, addition of a D1 agonist reduced GABA currents significantly more in D5 KO compared to D1 KO mice. We conclude that D1 receptors are the main D1-like receptor subtype involved in the modulation of GABA currents and that D5 receptors contribute to the normal expression of these currents in the striatum.


Dopamine Receptors GABA Knockout Mice Neuromodulation 



We thank Dr Véronique M. André for valuable suggestions and Christopher Calvert and Cynthia Chavira for their assistance in the organization of the data. Carol Gray and Donna Crandall helped with the illustrations. This study was supported by USPHS Grant NS33538.


  1. 1.
    Jackson DM, Westlind-Danielsson A (1994) Dopamine receptors: molecular biology, biochemistry and behavioral aspects. Pharmacol Ther 64:291–369PubMedCrossRefGoogle Scholar
  2. 2.
    Wise RA, Rompre PP (1994) Brain dopamine and reward. Annu Rev Psychol 40:191–225CrossRefGoogle Scholar
  3. 3.
    Arnsten AR, Cai JX, Steere JC, Goldman-Rakic PS (1995) Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys. J Neurosci 15:3429–3439PubMedGoogle Scholar
  4. 4.
    Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950PubMedCrossRefGoogle Scholar
  5. 5.
    Joel D, Weiner I (2000) The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience 96:451–474PubMedCrossRefGoogle Scholar
  6. 6.
    Cepeda C, Levine MS (1998) Dopamine and N-methyl-d-aspartate receptor interactions in the neostriatum. Dev Neurosci 20:1–18PubMedCrossRefGoogle Scholar
  7. 7.
    Missale C, Russel NS, Robinson WS, Jaber M, Caron GM (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225PubMedGoogle Scholar
  8. 8.
    Cepeda C, Buchwald NA, Levine MS (1993) Neuromodulatory actions of dopamine in the neostriatum are dependent upon the excitatory amino acid receptor subtypes activated. Proc Natl Acad Sci USA 90: 9576–9580PubMedCrossRefGoogle Scholar
  9. 9.
    Levine MS, Li Z, Cepeda C, Cromwell HC, Altemus KL (1996) Neuromodulatory actions of dopamine on synaptically-evoked neostriatal responses in slices. Synapse 24:65–78PubMedCrossRefGoogle Scholar
  10. 10.
    Hernandez-Echeagaray E, Starling AJ, Cepeda C, Levine MS (2004) Modulation of AMPA currents by D2 dopamine receptors in striatal medium-sized spiny neurons: are dendrites necessary? Eur J Neurosci 19:2455–2463PubMedCrossRefGoogle Scholar
  11. 11.
    Cepeda C, Colwell CS, Itri JN, Chandler SH, Levine MS (1998) Dopaminergic modulation of NMDA-induced whole cell currents in neostriatal neurons in slices: contribution of calcium conductances. J Neurophysiol 79:82–94PubMedGoogle Scholar
  12. 12.
    Yan Z, Hsieh-Wilson L, Feng J, Tomizawa K, Allen PB, Fienberg AA, Nairn AC, Greengard P (1999) Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. Nat Neurosci 2:13–17PubMedCrossRefGoogle Scholar
  13. 13.
    Flores-Hernandez J, Hernandez S, Snyder GT, Yan Z, Fienberg AA, Moss SJ, Greengard P, Surmeier DJ (2000) D1 Dopamine receptor activation reduces GABAA receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. J Neurophysiol 83:2996–3004PubMedGoogle Scholar
  14. 14.
    Daly G, Hawi Z, Fitzgerald M, Gill M (1999) Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol Psychiatry 4:192–196PubMedCrossRefGoogle Scholar
  15. 15.
    Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Waldman I, Fitzgerald M, Gill M (2002) Dopaminergic system genes in ADHD: toward a biological hypothesis. Neuropsychopharmacology 27:607–619PubMedGoogle Scholar
  16. 16.
    Muir WJ, Thomson ML, McKeon P, Mynett-Johnson L, Whitton C, Evans KL, Porteous DJ, Blackwood DH (2001) Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder. Am J Med Genet 105:152–158PubMedCrossRefGoogle Scholar
  17. 17.
    Ariano MA, Wang J, Noblett KL, Larson ER, Sibley DR (1997) Cellular distribution of the rat D1B receptor in central nervous system using anti-receptor antisera. Brain Res 746:141–150PubMedCrossRefGoogle Scholar
  18. 18.
    Khan ZU, Gutierrez A, Martin R, Penafiel A, Rivera A, de la Calle A (2000) Dopamine D5 receptors of rat and human brain. Neuroscience 100:689–699PubMedCrossRefGoogle Scholar
  19. 19.
    Ariano MA, Sibley DR (1994) Dopamine receptor distribution in the rat CNS: elucidation using anti-peptide antisera directed against D1A and D3 subtypes. Brain Res 649:95–110PubMedCrossRefGoogle Scholar
  20. 20.
    Ciliax BJ, Nash N, Heilman C, Sunahara R, Hartney A, Tiberi M, Rye DB, Caron MG, Niznik HB, Levey AI (2000) Dopamine D5 receptor immunolocalization in rat and monkey brain. Synapse 37:125–145PubMedCrossRefGoogle Scholar
  21. 21.
    Rivera A, Alberti I, Martin AB, Narvaez JA, de la Calle A, Moratalla R (2002) Molecular phenotype of rat striatal neurons expressing the dopamine D5 receptor subtype. Eur J Neurosci 16:2049–2058PubMedCrossRefGoogle Scholar
  22. 22.
    Berlanga ML, Simpson TK, Alcantara AA (2005) Dopamine D5 receptor localization on cholinergic neurons of the rat forebrain and diencephalon: a potential neuroanatomical substrate involved in mediating dopaminergic influences on acetylcholine release. J Comp Neurol 492:34–49PubMedCrossRefGoogle Scholar
  23. 23.
    Surmeier DJ, Song WJ, Yan Z (1996) Coordinated expression of dopamine receptors in neostriatal medium spiny neurons. J Neurosci 16:6579–6591PubMedGoogle Scholar
  24. 24.
    Hollon TR, Bek MJ, Lachowicz JE, Ariano MA, Mezey E, Ramachandran R, Wersinger SR, Soares-da-Silva P, Liu ZF, Grinberg A, Drago J, Young WS 3rd, Westphal H, Jose PA, Sibley DR (2002) Mice lacking D5 dopamine receptors have increased sympathetic tone and are hypertensive. J Neurosci 22:10801–10810PubMedGoogle Scholar
  25. 25.
    Holmes A, Hollon TR, Gleason TC, Liu Z, Dreiling J, Sibley DR, Crawley JN (2001) Behavioral characterization of dopamine D5 receptor null mutant mice. Behav Neurosci 115:1129–1144PubMedCrossRefGoogle Scholar
  26. 26.
    Elliot EE, Sibley DR, Katz JL (2003) Locomotor and discriminative-stimulus effects of cocaine in dopamine D5 receptor knockout mice. Psychopharmacology (Berl) 169:161–168CrossRefGoogle Scholar
  27. 27.
    O’Sullivan GJ, Kinsella A, Sibley DR, Tighe O, Croke DT, Waddington JL (2005) Ethological resolution of behavioural topography and D1-like versus D2-like agonist responses in congenic D5 dopamine receptor mutants: identification of D5:D2-like interactions. Synapse 55:201–211PubMedCrossRefGoogle Scholar
  28. 28.
    Baufreton J, Garret M, Rivera A, de la Calle A, Gonon F, Dufy B, Bioulac B, Taupignon A (2003) D5 (not D1) dopamine receptors potentiate burst-firing in neurons of the subthalamic nucleus by modulating an l-type calcium conductance. J Neurosci 23:816–825PubMedGoogle Scholar
  29. 29.
    Centonze D, Grande C, Saulle E, Martin AB, Gubellini P, Pavon N, Pisani A, Bernardi G, Moratalla R, Calabresi P (2003) Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity. J Neurosci 23:8506–8512PubMedGoogle Scholar
  30. 30.
    Levine MS, Altemus KL, Cepeda C, Cromwell HC, Crawford C, Ariano MA, Drago J, Sibley DR, Westphal H (1996) Modulatory actions of dopamine on NMDA receptor-mediated responses are reduced in D1A-deficient mutant mice. J Neurosci 16:5870–5882PubMedGoogle Scholar
  31. 31.
    Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850PubMedCrossRefGoogle Scholar
  32. 32.
    McDonald BJ, Amato A, Connolly CN, Benke D, Moss SJ, Smart TG (1998) Adjacent phosphorylation sites on GABAA receptor β subunits determine regulation by cAMP-dependent protein kinase. Nat Neurosci 1:23–28PubMedCrossRefGoogle Scholar
  33. 33.
    Drago J, Gerfen CR, Lachowicz JE, Steiner H, Hollon TR, Love PE, Ooi GT, Grinberg A, Lee EJ, Huang SP, Bartlett PF, Jose PA, Sibley DR, Westphal H (1994) Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc Natl Acad Sci USA 91:12564–12568PubMedCrossRefGoogle Scholar
  34. 34.
    Flores-Hernandez J, Cepeda C, Hernandez-Echeagaray E, Calvert CR, Jokel ES, Fienberg AA, Greengard P, Levine MS (2002) Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32. J Neurophysiol 88:3010–3020PubMedCrossRefGoogle Scholar
  35. 35.
    Liu F, Wan QI, Pristupa ZB, Yu XM, Wang YT, Niznik HB (2000) Direct protein-protein coupling enables cross-talk between dopamine D5 and γ-aminobutyric acid A receptors. Nature 403:274–280PubMedCrossRefGoogle Scholar
  36. 36.
    Hutcheon B, Fritschy JM, Poulter MO (2004) Organization of GABA receptor alpha-subunit clustering in the developing rat neocortex and hippocampus. Eur J Neurosci 19:2475–2487PubMedCrossRefGoogle Scholar
  37. 37.
    Nisembaum ES, Mermelstein PG, Wilson CJ, Surmeier DJ (1998) Selective blockade of a slowly inactivating potassium current in striatal neurons by ( ± ) 6-Cloro-APB hydrobromide (SKF 82958). Synapse 29:213–224CrossRefGoogle Scholar
  38. 38.
    Price CJ, Kim P, Raymond LA (1999) D1 Dopamine receptor-induced cyclic AMP-dependent protein kinase phosphorylation and potentiation of striatal glutamate receptors. J Neurochem 73:2441–2446PubMedCrossRefGoogle Scholar
  39. 39.
    Nicola SM, Malenka RC (1997) Dopamine depresses excitatory and inhibitory synaptic transmission by distinct mechanisms in the nucleus accumbens. J Neurosci 17:5697–5710PubMedGoogle Scholar
  40. 40.
    Nicola SM, Malenka RC (1998) Modulation of synaptic transmission by dopamine and norepinephrine in ventral but not dorsal striatum. J Neurophysiol 79: 1768–1776PubMedGoogle Scholar
  41. 41.
    Smith AD, Bolam JP (1990) The neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurons. Trends Neurosci 13:259–265PubMedCrossRefGoogle Scholar
  42. 42.
    Yan Z, Surmeier DJ (1997) D5 dopamine receptors enhance Zn2+ -sensitive GABAA currents in striatal cholinergic interneurons through a PKA/PP1 cascade. Nature 19:1115–1126Google Scholar
  43. 43.
    Cherubini E, Conti F (2001) Generating diversity at GABAergic synapses. Trends Neurosci 24:155–162PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Elizabeth Hernández-Echeagaray
    • 1
    • 4
  • Carlos Cepeda
    • 1
  • Marjorie A. Ariano
    • 2
  • Mary Kay Lobo
    • 1
  • David R. Sibley
    • 3
  • Michael S. Levine
    • 1
    Email author
  1. 1.Mental Retardation Research Center, Room 58-258 David Geffen School of MedicineUniversity of California Los AngelesLos AngelesUSA
  2. 2.Department of Neuroscience, Chicago Medical SchoolRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA
  3. 3.Molecular PharmacologyNIH/NINDSBethesdaUSA
  4. 4.Laboratorio de Neurofisiología del desarrollo y la NeurodegeneraciónUBIMED, FES-I, UNAMMexico CityMéxico

Personalised recommendations