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Title

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

Authors
Cruz, H. G.
Lujan, Rafael
Li, Meng
Yanagawa, Yuchio
Obata, Kunihiko
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Published in Nature Neuroscience. 2007, vol. 10, no. 12, p. 1559-1568
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 AnimalsAnimals, NewbornBaclofen/pharmacologyBarium Compounds/pharmacologyBehavior, Animal/drug effectsChlorides/pharmacologyDopamine/ metabolismDose-Response Relationship, DrugG Protein-Coupled Inwardly-Rectifying PotassiumChannels/genetics/ physiology/ultrastructureGABA Agonists/pharmacologyGlutamate Decarboxylase/geneticsGreen Fluorescent Proteins/geneticsHomeodomain Proteins/geneticsMembrane Potentials/drug effects/physiology/radiation effectsMiceMice, TransgenicMicroscopy, Electron, Transmission/methodsNeurons/ physiology/ultrastructurePatch-Clamp Techniques/methodsRGS Proteins/ metabolismReceptors, GABA-A/ physiologySodium Oxybate/pharmacologyTranscription Factors/geneticsVentral Tegmental Area/ cytology
Stable URL http://archive-ouverte.unige.ch/unige:10331
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PMID: 17965710
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