Journal
NATURE NEUROSCIENCE
Volume 10, Issue 12, Pages 1559-1568Publisher
NATURE RESEARCH
DOI: 10.1038/nn2006
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Funding
- Medical Research Council [MC_U120085817] Funding Source: Medline
- NIDA NIH HHS [P50 DA011806, DA011806] Funding Source: Medline
- NIMH NIH HHS [R01 MH061933, MH61933] Funding Source: Medline
- MRC [MC_U120085817] Funding Source: UKRI
- Medical Research Council [MC_U120085817] Funding Source: researchfish
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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.
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