Article (Published version) (1.2 MB) - Limited access to UNIGE
Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA.
|Published in||Neuron. 2012, vol. 73, no. 5, p. 978-89|
|Abstract||Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir(3)) channels, however, are poorly understood. Here, we show that 1 day after methamphetamine (METH) or cocaine exposure both synaptically evoked and baclofen-activated GABA(B)R-GIRK currents were significantly depressed in VTA GABA neurons and remained depressed for 7 days. Presynaptic inhibition mediated by GABA(B)Rs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABA(B1) and GIRK2, which occurred coincident with dephosphorylation of serine 783 (S783) in GABA(B2), a site implicated in regulating GABA(B)R surface expression. Inhibition of protein phosphatases recovered GABA(B)R-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABA(B)R signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system.|
|Keywords||Action Potentials/drug effects/genetics — Animals — Animals, Newborn — Baclofen/pharmacology — Bacterial Proteins/genetics/metabolism — Central Nervous System Stimulants/pharmacology — Dopamine/pharmacology — Dopamine Agents/pharmacology — Down-Regulation/drug effects — Drug Interactions — Female — G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism/ultrastructure — GABA-B Receptor Agonists/pharmacology — Glutamate Decarboxylase/genetics — Green Fluorescent Proteins/genetics/metabolism — Homeodomain Proteins/genetics — Inhibitory Postsynaptic Potentials/drug effects/genetics — Luminescent Proteins/genetics/metabolism — Male — Methamphetamine/pharmacology — Mice — Mice, Inbred C57BL — Mice, Transgenic — Microscopy, Immunoelectron/methods — Neurons/drug effects/metabolism/ultrastructure — Organophosphorus Compounds/pharmacology — Phosphorylation — Receptors, GABA-A/metabolism/ultrastructure — Rhodopsin/genetics/metabolism — Transcription Factors/genetics — Ventral Tegmental Area/cytology/drug effects — Gamma-Aminobutyric Acid/metabolism/pharmacology|
|Research group||Mécanismes cellulaires de la dépendance et de l'addiction (520)|
|PADGETT, Claire L et al. Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA. In: Neuron, 2012, vol. 73, n° 5, p. 978-89. https://archive-ouverte.unige.ch/unige:26960|