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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Baclofen / pharmacology
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Barium Compounds / pharmacology
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Behavior, Animal / drug effects
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Chlorides / pharmacology
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Dopamine / metabolism*
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Dose-Response Relationship, Drug
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G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
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G Protein-Coupled Inwardly-Rectifying Potassium Channels / physiology*
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G Protein-Coupled Inwardly-Rectifying Potassium Channels / ultrastructure
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GABA Agonists / pharmacology
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Glutamate Decarboxylase / genetics
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Green Fluorescent Proteins / genetics
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Homeodomain Proteins / genetics
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In Vitro Techniques
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission / methods
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Neurons / physiology*
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Neurons / ultrastructure
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Patch-Clamp Techniques / methods
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RGS Proteins / metabolism*
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Receptors, GABA-A / physiology*
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Sodium Oxybate / pharmacology
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Transcription Factors / genetics
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Ventral Tegmental Area / cytology*
Substances
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Barium Compounds
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Chlorides
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G Protein-Coupled Inwardly-Rectifying Potassium Channels
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GABA Agonists
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Homeodomain Proteins
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RGS Proteins
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Receptors, GABA-A
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Rgs2 protein, mouse
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Transcription Factors
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homeobox protein PITX3
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barium chloride
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Green Fluorescent Proteins
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Sodium Oxybate
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Glutamate Decarboxylase
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glutamate decarboxylase 1
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Baclofen
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Dopamine