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Title

Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA.

Authors
Padgett, Claire L
Terunuma, Miho
Munoz, Michaelanne B
Pangalos, Menelas N
Martínez-Hernández, José
Watanabe, Masahiko
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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/geneticsAnimalsAnimals, NewbornBaclofen/pharmacologyBacterial Proteins/genetics/metabolismCentral Nervous System Stimulants/pharmacologyDopamine/pharmacologyDopamine Agents/pharmacologyDown-Regulation/drug effectsDrug InteractionsFemaleG Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism/ultrastructureGABA-B Receptor Agonists/pharmacologyGlutamate Decarboxylase/geneticsGreen Fluorescent Proteins/genetics/metabolismHomeodomain Proteins/geneticsInhibitory Postsynaptic Potentials/drug effects/geneticsLuminescent Proteins/genetics/metabolismMaleMethamphetamine/pharmacologyMiceMice, Inbred C57BLMice, TransgenicMicroscopy, Immunoelectron/methodsNeurons/drug effects/metabolism/ultrastructureOrganophosphorus Compounds/pharmacologyPhosphorylationReceptors, GABA-A/metabolism/ultrastructureRhodopsin/genetics/metabolismTranscription Factors/geneticsVentral Tegmental Area/cytology/drug effectsGamma-Aminobutyric Acid/metabolism/pharmacology
Identifiers
PMID: 22405207
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Structures
Research group Mécanismes cellulaires de la dépendance et de l'addiction (520)
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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

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Deposited on : 2013-03-25

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