Skip to main content
Log in

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

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

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.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Jackson DM, Westlind-Danielsson A (1994) Dopamine receptors: molecular biology, biochemistry and behavioral aspects. Pharmacol Ther 64:291–369

    Article  PubMed  CAS  Google Scholar 

  2. Wise RA, Rompre PP (1994) Brain dopamine and reward. Annu Rev Psychol 40:191–225

    Article  Google Scholar 

  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 15:3429–3439

    PubMed  CAS  Google Scholar 

  4. 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 

  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 96:451–474

    Article  PubMed  CAS  Google Scholar 

  6. Cepeda C, Levine MS (1998) Dopamine and N-methyl-d-aspartate receptor interactions in the neostriatum. Dev Neurosci 20:1–18

    Article  PubMed  CAS  Google Scholar 

  7. Missale C, Russel NS, Robinson WS, Jaber M, Caron GM (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225

    PubMed  CAS  Google Scholar 

  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: 9576–9580

    Article  PubMed  CAS  Google Scholar 

  9. Levine MS, Li Z, Cepeda C, Cromwell HC, Altemus KL (1996) Neuromodulatory actions of dopamine on synaptically-evoked neostriatal responses in slices. Synapse 24:65–78

    Article  PubMed  CAS  Google Scholar 

  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 19:2455–2463

    Article  PubMed  Google Scholar 

  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 79:82–94

    PubMed  CAS  Google Scholar 

  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 2:13–17

    Article  PubMed  CAS  Google Scholar 

  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 83:2996–3004

    PubMed  CAS  Google Scholar 

  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 4:192–196

    Article  PubMed  CAS  Google Scholar 

  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 27:607–619

    PubMed  CAS  Google Scholar 

  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 105:152–158

    Article  PubMed  CAS  Google Scholar 

  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 746:141–150

    Article  PubMed  CAS  Google Scholar 

  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 100:689–699

    Article  PubMed  CAS  Google Scholar 

  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 649:95–110

    Article  PubMed  CAS  Google Scholar 

  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 37:125–145

    Article  PubMed  CAS  Google Scholar 

  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 16:2049–2058

    Article  PubMed  Google Scholar 

  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 492:34–49

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  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 22:10801–10810

    PubMed  CAS  Google Scholar 

  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 115:1129–1144

    Article  PubMed  CAS  Google Scholar 

  26. Elliot EE, Sibley DR, Katz JL (2003) Locomotor and discriminative-stimulus effects of cocaine in dopamine D5 receptor knockout mice. Psychopharmacology (Berl) 169:161–168

    Article  CAS  Google Scholar 

  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 55:201–211

    Article  PubMed  CAS  Google Scholar 

  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 23:816–825

    PubMed  CAS  Google Scholar 

  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 23:8506–8512

    PubMed  CAS  Google Scholar 

  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 16:5870–5882

    PubMed  CAS  Google Scholar 

  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 101:815–850

    Article  PubMed  CAS  Google Scholar 

  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 1:23–28

    Article  PubMed  CAS  Google Scholar 

  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 91:12564–12568

    Article  PubMed  CAS  Google Scholar 

  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 88:3010–3020

    Article  PubMed  CAS  Google Scholar 

  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 403:274–280

    Article  PubMed  CAS  Google Scholar 

  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 19:2475–2487

    Article  PubMed  CAS  Google Scholar 

  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 29:213–224

    Article  Google Scholar 

  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 73:2441–2446

    Article  PubMed  CAS  Google Scholar 

  39. Nicola SM, Malenka RC (1997) Dopamine depresses excitatory and inhibitory synaptic transmission by distinct mechanisms in the nucleus accumbens. J Neurosci 17:5697–5710

    PubMed  CAS  Google Scholar 

  40. Nicola SM, Malenka RC (1998) Modulation of synaptic transmission by dopamine and norepinephrine in ventral but not dorsal striatum. J Neurophysiol 79: 1768–1776

    PubMed  CAS  Google Scholar 

  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 13:259–265

    Article  PubMed  CAS  Google Scholar 

  42. Yan Z, Surmeier DJ (1997) D5 dopamine receptors enhance Zn2+ -sensitive GABAA currents in striatal cholinergic interneurons through a PKA/PP1 cascade. Nature 19:1115–1126

    CAS  Google Scholar 

  43. Cherubini E, Conti F (2001) Generating diversity at GABAergic synapses. Trends Neurosci 24:155–162

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael S. Levine.

Additional information

Special issue dedicated to Anthony Campagnoni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hernández-Echeagaray, E., Cepeda, C., Ariano, M.A. et al. Dopamine Reduction of GABA Currents in Striatal Medium-sized Spiny Neurons is Mediated Principally by the D1 Receptor Subtype. Neurochem Res 32, 229–240 (2007). https://doi.org/10.1007/s11064-006-9141-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9141-8

Keywords

Navigation