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RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area

Nature Neuroscience volume 10, pages 1559–1568 (2007)Cite this article

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Abstract

Agonists of GABAB receptors exert a bi-directional effect on the activity of dopamine (DA) neurons of the ventral tegmental area, which can be explained by the fact that coupling between GABAB receptors and G protein-gated inwardly rectifying potassium (GIRK) channels is significantly weaker in DA neurons than in GABA neurons. Thus, low concentrations of agonists preferentially inhibit GABA neurons and thereby disinhibit DA neurons. This disinhibition might confer reinforcing properties on addictive GABAB receptor agonists such as γ-hydroxybutyrate (GHB) and its derivatives. Here we show that, in DA neurons of mice, the low coupling efficiency reflects the selective expression of heteromeric GIRK2/3 channels and is dynamically modulated by a member of the regulator of G protein signaling (RGS) protein family. Moreover, repetitive exposure to GHB increases the GABAB receptor-GIRK channel coupling efficiency through downregulation of RGS2. Finally, oral self-administration of GHB at a concentration that is normally rewarding becomes aversive after chronic exposure. On the basis of these results, we propose a mechanism that might underlie tolerance to GHB.

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Figure 1: Baclofen-evoked currents in DA and GABA neurons of the VTA.
Figure 2: Cell-type-specific subcellular localization of GIRK subunits.
Figure 3: Contribution of GIRK channel subunits to total outward current in DA neurons of the VTA.
Figure 4: GABAB-GIRK coupling efficiency in DA neurons is determined by GIRK subunit expression.
Figure 5: Inhibition of RGS proteins increases the GABAB-GIRK coupling efficiency in DA neurons.
Figure 6: RGS2 modulates GABAB-GIRK coupling in DA neurons.
Figure 7: Close association between RGS2 proteins and GIRK3 channels.
Figure 8: Exposure to GHB and morphine modulates GABAB-GIRK coupling efficiency by reducing the transcription level of RGS2.
Figure 9: Bi-directional effects of GABAB receptor agonists on the firing rate of DA neurons in the VTA.
Figure 10: Previous chronic exposure to GHB alters preference for oral self-administration of GHB.

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  • 14 November 2007

    In the version of this article initially published online, the corresponding author's email address was incorrect. The correct email address is Christian.Luscher@medecine.unige.ch. The error has been corrected for all versions of the article.

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Acknowledgements

We thank M. Serafin and the members of the Lüscher lab for discussions, F. Loctin and M. J. Cabañero for technical assistance and V. Ossipow for help with the real-time PCR. We thank M. Stoffel for the GIRK2−/− mice and J. Penninger for the RGS2−/− mice. CFP-Kir3.4 and Kir3.1-YFP cDNAs were provided by E. Reuveny. This work was supported by the Swiss National Science Foundation (C.L.), NIDA (P.A.S. and C.L.), and a grant from the Spanish Ministry of Education and Science (R.L.). Additional support comes from DA011806 and MH61933 (K.W.), and by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, Japan (Y.Y.).

Author information

Author notes

  1. Gwenaël Labouèbe, Marta Lomazzi and Hans G Cruz: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1, Michel- Servet, Geneva, CH-1211, Switzerland

    Gwenaël Labouèbe, Marta Lomazzi, Hans G Cruz, Cyril Creton & Christian Lüscher

  2. Department of Medical Sciences, Faculty of Medecine-CRIB, University of Castilla-La Mancha, Avenida de Almansa s/n, Albacete, 02006, Spain

    Rafael Luján

  3. MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Meng Li

  4. Department of Genetic and Behavioural Neuroscience, Gunma University Graduate School of Medicine, 39-22, Showa-machi 3-chome, Maebashi, 371-8511, Gunma, Japan

    Yuchio Yanagawa

  5. RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, 351-0198, Saitama, Japan

    Kunihiko Obata

  6. Department of Anatomy, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, 060-8638, Sapporo, Japan

    Masahiko Watanabe

  7. Department of Pharmacology, University of Minnesota, 312 Church Street SE Minneapolis, 55455, Minnesota, USA

    Kevin Wickman

  8. The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Stephanie B Boyer & Paul A Slesinger

  9. Department of Clinical Neurosciences, Clinic of Neurology, Geneva University Hospital, 24, Micheli-du-Crest, CH-1211, Geneva, Switzerland

    Christian Lüscher

Authors
  1. Gwenaël Labouèbe
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Contributions

G.L., M. Lomazzi and H.G.C. carried out all the electrophysiology experiments and participated in the preparation of the manuscript. G.L. performed the stereotactic viral injections. M. Lomazzi did all the PCR experiments. C.C. carried out the behavioral experiments. R.L. did the light microscope immunohistochemistry and the double-labeling electron microscope immunoreactions using an antibody raised by M.W., M. Li, Y.Y., K.O. and K.W. provided transgenic mouse lines. S.B.B. did the FRET experiments. C.L. designed the study in collaboration with P.A.S. and wrote the core of the manuscript.

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Correspondence to Christian Lüscher.

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Labouèbe, G., Lomazzi, M., Cruz, H. et al. RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nat Neurosci 10, 1559–1568 (2007). https://doi.org/10.1038/nn2006

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