Bi-directional effects of GABA<sub>B</sub> receptor agonists on the mesolimbic dopamine system

Article Article scientifique Article Bi-directional effects of GABA<sub>B</sub> receptor agonists on the mesolimbic dopamine system eng 2004 author Cruz Hans G. author Ivanova Tatiana 558687 author Lunn Marie Louise author Stoffel Markus author Slesinger Paul A. author Luescher Christian 132337 Département de neurosciences fondamentales (NEUFO) 153-159 10.1038/nn1181 14745451 1097-6256 http://www.nature.com/neuro/journal/v7/n2/pdf/nn1181.pdf 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. Animals Baclofen / pharmacology Dopamine / metabolism G Protein-Coupled Inwardly-Rectifying Potassium Channels GABA Agonists / pharmacology GABA-B Receptor Agonists Humans Hydroxybutyrates / pharmacology Mice Neurons / drug effects Neurons / physiology Organ Culture Techniques Patch-Clamp Techniques Potassium Channels / drug effects Potassium Channels / physiology Potassium Channels, Inwardly Rectifying Rats Receptors, GABA-B / drug effects Receptors, GABA-B / physiology Reverse Transcriptase Polymerase Chain Reaction Transfection Ventral Tegmental Area / drug effects Ventral Tegmental Area / physiology Dewey 616.8 53 Département de neurosciences fondamentales 21A false 271 Mécanismes cellulaires de la dépendance et de l'addiction 520 http://www.ncbi.nlm.nih.gov/nuccore/?term=AB073753 http://www.ncbi.nlm.nih.gov/nuccore/?term=AB073754 http://www.ncbi.nlm.nih.gov/nuccore/?term=AB073756 http://www.ncbi.nlm.nih.gov/nuccore/?term=L22651 http://www.ncbi.nlm.nih.gov/nuccore/?term=L35771 http://www.ncbi.nlm.nih.gov/nuccore/?term=L77929 http://www.ncbi.nlm.nih.gov/nuccore/?term=M76177 http://www.ncbi.nlm.nih.gov/nuccore/?term=U09243 Nature neuroscience 7 2 4b66c95e-73d9-4072-83a8-5e8c84e16755 Article (Published version) Restricted file1.pdf 528807 application/pdf e7773dbc-ad79-484c-aca2-06026b459a1e Article (Accepted version) Public 1._Cruz_Nat_Neurosci_2004.pdf 855785 application/pdf Restricted 2005-07-01 86c711957141033cfeee8b1f727cff91ccbda960e5c1a22f3d54c531041e40a2 801b1832-b0ae-4d35-b055-e05e8f41b6f1 Appendix Restricted 41593_2004_BFnn1181_MOESM1_ESM.gif 5936 image/gif Supplementary Fig. 1 dc35a88cfe744e2bc6bd5350a1070d988f59171e2044b94aa52b6b372858dd18 f652f905-1d33-4273-a7d0-5c0cc383863b Appendix Restricted 41593_2004_BFnn1181_MOESM2_ESM.jpg 73375 image/jpeg Supplementary Fig. 2 a81176224f08f54b9a382319ae1cd73873931580e9039994cfb213e9cb9e17f7 openAccess Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales

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Bi-directional effects of GABA_B receptor agonists on the mesolimbic dopamine system	Nature neuroscience			2004	620	56

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Ivanova, Tatiana