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

2012; Cell Press; Volume: 73; Issue: 5 Linguagem: Inglês

10.1016/j.neuron.2011.12.031

1097-4199

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,

Receptor Mechanisms and Signaling

Summary 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.