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

Neuron. 2012 Mar 8;73(5):978-89. doi: 10.1016/j.neuron.2011.12.031.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Animals, Newborn
  • Baclofen / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Central Nervous System Stimulants / pharmacology*
  • Channelrhodopsins
  • Dopamine / pharmacology
  • Dopamine Agents / pharmacology
  • Down-Regulation / drug effects*
  • Drug Interactions
  • Female
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / ultrastructure
  • GABA-B Receptor Agonists / pharmacology
  • Glutamate Decarboxylase / genetics
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / genetics
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / genetics
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Methamphetamine / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Immunoelectron / methods
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Organophosphorus Compounds / pharmacology
  • Phosphorylation
  • Receptors, GABA-A / metabolism*
  • Receptors, GABA-A / ultrastructure
  • Transcription Factors / genetics
  • Ventral Tegmental Area / cytology*
  • Ventral Tegmental Area / drug effects
  • gamma-Aminobutyric Acid / metabolism*
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Bacterial Proteins
  • Central Nervous System Stimulants
  • Channelrhodopsins
  • Dopamine Agents
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • GABA-B Receptor Agonists
  • Homeodomain Proteins
  • Kcnj6 protein, mouse
  • Luminescent Proteins
  • Organophosphorus Compounds
  • Receptors, GABA-A
  • Transcription Factors
  • homeobox protein PITX3
  • yellow fluorescent protein, Bacteria
  • Green Fluorescent Proteins
  • CGP 54626
  • Methamphetamine
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • Baclofen
  • Dopamine