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Research Articles, Systems/Circuits

Projection-Specific Potentiation of Ventral Pallidal Glutamatergic Outputs after Abstinence from Cocaine

Liran A. Levi, Kineret Inbar, Noa Nachshon, Nimrod Bernat, Ava Gatterer, Dorrit Inbar and Yonatan M. Kupchik
Journal of Neuroscience 5 February 2020, 40 (6) 1276-1285; https://doi.org/10.1523/JNEUROSCI.0929-19.2019
Liran A. Levi
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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Kineret Inbar
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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Noa Nachshon
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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Nimrod Bernat
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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Ava Gatterer
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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Dorrit Inbar
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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Yonatan M. Kupchik
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
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This article has a correction. Please see:

  • Erratum: Levi et al., “Projection-Specific Potentiation of Ventral Pallidal Glutamatergic Outputs after Abstinence from Cocaine” - April 30, 2020

Abstract

The ventral pallidum (VP) is a central node in the reward system that is strongly implicated in reward and addiction. Although the majority of VP neurons are GABAergic and encode reward, recent studies revealed a novel glutamatergic neuronal population in the VP [VP neurons expressing the vesicular glutamate transporter 2 (VPVGluT2)], whose activation generates aversion. Withdrawal from drugs has been shown to induce drastic synaptic changes in neuronal populations associated with reward, such as the ventral tegmental area (VTA) or nucleus accumbens neurons, but less is known about cocaine-induced synaptic changes in neurons classically linked with aversion. Here, we demonstrate that VPVGluT2 neurons contact different targets with different intensities, and that cocaine conditioned place preference (CPP) training followed by abstinence selectively potentiates their synapses on targets that encode aversion. Using whole-cell patch-clamp recordings combined with optogenetics in male and female transgenic mice, we show that VPVGluT2 neurons preferentially contact aversion-related neurons, such as lateral habenula neurons and VTA GABAergic neurons, with minor input to reward-related neurons, such as VTA dopamine and VP GABA neurons. Moreover, after cocaine CPP and abstinence, the VPVGluT2 input to the aversion-related structures is potentiated, whereas the input to the reward-related structures is depressed. Thus, cocaine CPP followed by abstinence may allow VPVGluT2 neurons to recruit aversion-related targets more readily and therefore be part of the mechanism underlying the aversive symptoms seen after withdrawal.

SIGNIFICANCE STATEMENT The biggest problem in drug addiction is the high propensity to relapse. One central driver for relapse events is the negative aversive symptoms experienced by addicts during withdrawal. In this work, we propose a possible mechanism for the intensification of aversive feelings after withdrawal that involves the glutamatergic neurons of the ventral pallidum. We show not only that these neurons are most strongly connected to aversive targets, such as the lateral habenula, but also that, after abstinence, their synapses on aversive targets are strengthened, whereas the synapses on other rewarding targets are weakened. These data illustrate how after abstinence from cocaine, aversive pathways change in a manner that may contribute to relapse.

  • Ventral pallidum
  • VGluT2 neurons
  • Lateral habenula
  • cocaine
  • slice electrophysiology
  • optogenetics
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The Journal of Neuroscience: 40 (6)
Journal of Neuroscience
Vol. 40, Issue 6
5 Feb 2020
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Projection-Specific Potentiation of Ventral Pallidal Glutamatergic Outputs after Abstinence from Cocaine
Liran A. Levi, Kineret Inbar, Noa Nachshon, Nimrod Bernat, Ava Gatterer, Dorrit Inbar, Yonatan M. Kupchik
Journal of Neuroscience 5 February 2020, 40 (6) 1276-1285; DOI: 10.1523/JNEUROSCI.0929-19.2019

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Projection-Specific Potentiation of Ventral Pallidal Glutamatergic Outputs after Abstinence from Cocaine
Liran A. Levi, Kineret Inbar, Noa Nachshon, Nimrod Bernat, Ava Gatterer, Dorrit Inbar, Yonatan M. Kupchik
Journal of Neuroscience 5 February 2020, 40 (6) 1276-1285; DOI: 10.1523/JNEUROSCI.0929-19.2019
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Keywords

  • ventral pallidum
  • VGluT2 neurons
  • lateral habenula
  • cocaine
  • slice electrophysiology
  • optogenetics

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