title: Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA.
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.
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Padgett
authors.forename: Arnaud L
authors.initials: AL
authors.lastname: Lalive
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Tan
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.forename: Michaelanne B
authors.initials: MB
authors.lastname: Munoz
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: José
authors.initials: J
authors.lastname: Martínez-Hernández
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
authors.forename: Paul A
authors.initials: PA
authors.lastname: Slesinger
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001418:Baclofen / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D000075402:Channelrhodopsins; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004347:Drug Interactions; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism / Q000648:ultrastructure; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000648:ultrastructure; D014157:Transcription Factors / Q000235:genetics; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D000697:Central Nervous System Stimulants; D000075402:Channelrhodopsins; D015259:Dopamine Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D058786:GABA-B Receptor Agonists; D018398:Homeodomain Proteins; C497069:Kcnj6 protein, mouse; D008164:Luminescent Proteins; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D014157:Transcription Factors; C433629:homeobox protein PITX3; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; C107353:CGP 54626; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D001418:Baclofen; D004298:Dopamine