Agonists of GABAB 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 GABAB 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 GABAB receptor agonists such as γ-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 GABAB 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.
Bibliographical noteFunding Information:
We thank M. Serafin and the members of the Lüscher lab for discussions, F. Loctin and M. J. Cabañero for technical assistance and V. Ossipow for help with the real-time PCR. We thank M. Stoffel for the GIRK2–/– mice and J. Penninger for the RGS2–/– mice. CFP-Kir3.4 and Kir3.1-YFP cDNAs were provided by E. Reuveny. This work was supported by the Swiss National Science Foundation (C.L.), NIDA (P.A.S. and C.L.), and a grant from the Spanish Ministry of Education and Science (R.L.). Additional support comes from DA011806 and MH61933 (K.W.), and by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, Japan (Y.Y.).