TY - JOUR
T1 - Methamphetamine-Evoked Depression of GABA B Receptor Signaling in GABA Neurons of the VTA
AU - Padgett, Claire L.
AU - Lalive, Arnaud L.
AU - Tan, Kelly R.
AU - Terunuma, Miho
AU - Munoz, Michaelanne B.
AU - Pangalos, Menelas N.
AU - Martínez-Hernández, José
AU - Watanabe, Masahiko
AU - Moss, Stephen J.
AU - Luján, Rafael
AU - Lüscher, Christian
AU - Slesinger, Paul A.
N1 - Funding Information:
We thank all members of the Slesinger and Lüscher laboratories, as well as G.O. Hjelmstad for comments on the manuscript. This work was supported by grants from the Salk Institute's Catharina Foundation (Postdoctoral Fellowship to C.L.P.), the Spanish Ministry of Education and Science (BFU-2009-08404 to R.L.) and Consolider (CSD2008-00005 to R.L.), the National Institute of Neurological Disorders and Stroke (NS048045, NS051195, NS056359, and NS054900 to S.J.M.), a Ruth L. Kirschstein National Research Service Award (F31 DA029401 to M.B.M) and the National Institute on Drug Abuse (DA019022 to P.A.S. and C.L.; DA025236 to P.A.S.).
PY - 2012/3/8
Y1 - 2012/3/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84858042525&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2011.12.031
DO - 10.1016/j.neuron.2011.12.031
M3 - Article
C2 - 22405207
AN - SCOPUS:84858042525
SN - 0896-6273
VL - 73
SP - 978
EP - 989
JO - Neuron
JF - Neuron
IS - 5
ER -