Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system.
The rewarding effect of drugs of abuse is mediated by activation of the mesolimbic dopamine system, which is inhibited by putative anti-craving compounds. Interestingly, different GABA(B) receptor agonists can exert similarly opposing effects on the reward pathway, but the cellular mechanisms involved are unknown. Here we found that the coupling efficacy (EC(50)) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABA(B) receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits. Consequently, in rodent VTA slices, a low concentration of the canonical agonist baclofen caused increased activity, whereas higher doses eventually inhibited dopamine neurons. At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse gamma-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons. Thus GABA(B) receptor agonists exert parallel cellular and behavioral effects due to the cell-specific expression of GIRK subunits.
Cruz
Hans G
HG
Department of Basic Neurosciences, University of Geneva, 1 Michel Servet, CH-1211 Geneva 4, Switzerland.
Ivanova
Tatiana
T
Lunn
Marie-Louise
ML
Stoffel
Markus
M
Slesinger
Paul A
PA
Lüscher
Christian
C
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018755:GABA Agonists / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D006885:Hydroxybutyrates; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D018080:Receptors, GABA-B; C111420:4-hydroxybutyric acid; D001418:Baclofen; D004298:Dopamine