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

• DOI: 10.1016/j.neuron.2011.12.031
• Publication Date: 2012-03-07T22:32:29Z
• Authors: Claire L. Padgett; Arnaud L. Lalive; Kelly R. Tan; Miho Terunuma; Michaelanne B. Munoz; Menelas N. Pangalos; José Martínez-Her...; Masahiko Watanabe; Stephen J. Moss; Rafael Luján; Christian Lüscher; Paul A. Slesinger
• Keywords: Male; Baclofen; Dopamine; Dopamine Agents; Down-Regulation/drug effects; Action Potentials; GABA-B Receptor Agonists/pharmacology; Receptors, GABA-A/metabolism/ultrastructure; Mice; Drug Interactions; Phosphorylation; Dopamine/pharmacology; 0303 health sciences; Dopamine Agents/pharmacology; Action Potentials/drug effects/genetics; Glutamate Decarboxylase; Microscopy, Immunoelectron/methods; info:eu-repo/classification/ddc/616.8; Bacterial Proteins/genetics/metabolism; Female; Organophosphorus Compounds/pharmacology; Neuroscience(all); Rhodopsin/genetics/metabolism; Green Fluorescent Proteins; Transcription Factors/genetics; Down-Regulation; Mice, Transgenic; In Vitro Techniques; Baclofen/pharmacology; Glutamate Decarboxylase/genetics; Gamma-Aminobutyric Acid/metabolism/pharmacology; 03 medical and health sciences; Bacterial Proteins; Channelrhodopsins; Green Fluorescent Proteins/genetics/metabolism; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism/ultrastructure; Neurons/drug effects/metabolism/ultrastructure; Animals; Luminescent Proteins/genetics/metabolism; Homeodomain Proteins; Ventral Tegmental Area/cytology/drug effects; ddc:616.8; Mice, Inbred C57BL; Luminescent Proteins; Animals, Newborn; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Inhibitory Postsynaptic Potentials; GABA-B Receptor Agonists; Inhibitory Postsynaptic Potentials/drug effects/genetics; Methamphetamine/pharmacology; Central Nervous System Stimulants/pharmacology; Central Nervous System Stimulants; Homeodomain Proteins/genetics

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.