Referenced in: none

Automatically associated channels: Kir2.2 , Kir3.2

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

Authors: Gwenaël Labouèbe, Marta Lomazzi, Hans G Cruz, Cyril Creton, Rafael Lujan, Meng Li, Yuchio Yanagawa, Kunihiko Obata, Masahiko Watanabe, Kevin Wickman, Stephanie B Boyer, Paul A Slesinger, Christian Lüscher

Journal, date & volume: Nat. Neurosci., 2007 Dec , 10, 1559-68

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17965710

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.