Article abstract
Nature Neuroscience 10, 1559 - 1568 (2007)
Published online: 28 October 2007 | Corrected online: 14 November 2007 | doi:10.1038/nn2006
RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area
Gwenaël Labouèbe1,10, Marta Lomazzi1,10, Hans G Cruz1,10, Cyril Creton1, Rafael Luján2, Meng Li3, Yuchio Yanagawa4, Kunihiko Obata5, Masahiko Watanabe6, Kevin Wickman7, Stephanie B Boyer8, Paul A Slesinger8 & Christian Lüscher1,9
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 
-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.
- Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1, Michel- Servet, CH-1211 Geneva, Switzerland.
- Department of Medical Sciences, Faculty of Medecine-CRIB, University of Castilla-La Mancha, Avenida de Almansa s/n, 02006 Albacete, Spain.
- MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
- Department of Genetic and Behavioural Neuroscience, Gunma University Graduate School of Medicine, 39-22, Showa-machi 3-chome, Maebashi, Gunma 371-8511, Japan.
- RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
- Department of Anatomy, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan.
- Department of Pharmacology, University of Minnesota, 312 Church Street SE Minneapolis, Minnesota 55455, USA.
- The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
- Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, 24, Micheli-du-Crest, CH-1211 Geneva, Switzerland.
- These authors contributed equally to this work.
Correspondence to: Christian Lüscher1,9 e-mail: Christian.Luscher@medecine.unige.cn
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