Methamphetamine-Evoked Depression of GABA B Receptor Signaling in GABA Neurons of the VTA

Claire L. Padgett, Arnaud L. Lalive, Kelly R. Tan, Miho Terunuma, Michaelanne B. Munoz, Menelas N. Pangalos, José Martínez-Hernández, Masahiko Watanabe, Stephen J. Moss, Rafael Luján, Christian Lüscher, Paul A. Slesinger

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 BR-GIRK currents were significantly depressed in VTA GABA neurons and remained depressed for 7 days. Presynaptic inhibition mediated by GABA BRs 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 BR surface expression. Inhibition of protein phosphatases recovered GABA BR-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABA BR signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system. Mechanisms underlying drug-evoked plasticity of slow inhibitory transmission mediated by GABA B receptors and G protein-gated inwardly rectifying potassium (GIRK) channels are poorly understood. Padgett et al. describe a mechanism by which methamphetamine depresses GABA BR-GIRK signaling in VTA GABA neurons.

Original languageEnglish
Pages (from-to)978-989
Number of pages12
JournalNeuron
Volume73
Issue number5
DOIs
StatePublished - 8 Mar 2012
Externally publishedYes

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