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Scientific article
English

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

Contributors

Labouebe, Gwenael Pierre; Lomazzi, Marta; Cruz, H. G.; Creton, Cyril; Lujan, Rafael; Li, Meng; Yanagawa, Yuchio; Obata, Kunihiko; Watanabe, Masahiko; Wickman, Kevin; Boyer, S. B.; Slesinger, P. A.; Luescher, Christian

Published in

Nature neuroscience, vol. 10, no. 12, p. 1559-1568

Publication date

2007

Abstract

Agonists of GABA(B) 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 GABA(B) 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 GABA(B) receptor agonists such as gamma-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 GABA(B) 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.

Keywords

  • Animals
  • Animals, Newborn
  • Baclofen/pharmacology
  • Barium Compounds/pharmacology
  • Behavior, Animal/drug effects
  • Chlorides/pharmacology
  • Dopamine/ metabolism
  • Dose-Response Relationship, Drug
  • G Protein-Coupled Inwardly-Rectifying Potassium
  • Channels/genetics/ physiology/ultrastructure
  • GABA Agonists/pharmacology
  • Glutamate Decarboxylase/genetics
  • Green Fluorescent Proteins/genetics
  • Homeodomain Proteins/genetics
  • Membrane Potentials/drug effects/physiology/radiation effects
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission/methods
  • Neurons/ physiology/ultrastructure
  • Patch-Clamp Techniques/methods
  • RGS Proteins/ metabolism
  • Receptors, GABA-A/ physiology
  • Sodium Oxybate/pharmacology
  • Transcription Factors/genetics
  • Ventral Tegmental Area/ cytology

UNIGE affiliation entities

Citation (ISO format)

LABOUEBE, Gwenael Pierre et al. RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. In: Nature neuroscience, 2007, vol. 10, n° 12, p. 1559–1568. doi: 10.1038/nn2006

Main files (1)

Article

Identifiers

Additional URL for this publication

http://www.nature.com/neuro/journal/v10/n12/pdf/nn2006.pdf

Journal ISSN

1097-6256
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Technical informations

Creation

06/08/2010 13:47:01

First validation

06/08/2010 13:47:01

Update

14/10/2025 05:54:26

Status update

14/03/2023 15:58:49

Last indexation

02/11/2026 16:36:41
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