Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement

  1. Julie Corre
  2. Ruud van Zessen
  3. Michaël Loureïro
  4. Tommaso Patriarchi
  5. Lin Tian
  6. Vincent Pascoli
  7. Christian Lüscher  Is a corresponding author
  1. University of Geneva, Switzerland
  2. University of California, Davis, United States

Abstract

The dopamine (DA) hypothesis posits the increase of mesolimbic dopamine levels as a defining commonality of addictive drugs, initially causing reinforcement, eventually leading to compulsive consumption. While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we monitor genetically encoded DA and calcium indicators as well as cFos in mice to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.

Data availability

The raw data are available via Zenodo (https://zenodo.org/record/1471574#.W9K7YfaYSUk)

The following data sets were generated

Article and author information

Author details

  1. Julie Corre

    Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Ruud van Zessen

    Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Michaël Loureïro

    Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5915-5627
  4. Tommaso Patriarchi

    Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lin Tian

    Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7012-6926
  6. Vincent Pascoli

    Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Christian Lüscher

    Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
    For correspondence
    Christian.Luscher@unige.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7917-4596

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B_170266)

  • Christian Lüscher

European Commission (MeSSI)

  • Christian Lüscher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with Swiss law (LPA). All of the animals were handled according to approved institutional animal care and use committee of Unige. The protocol was approved by the Committee on the Ethics of Animal Experiments of canton of Geneva (Permit Number: GE-128-16). Every effort was made to minimize suffering.

Copyright

© 2018, Corre et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 10,476
    views
  • 1,384
    downloads
  • 143
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Julie Corre
  2. Ruud van Zessen
  3. Michaël Loureïro
  4. Tommaso Patriarchi
  5. Lin Tian
  6. Vincent Pascoli
  7. Christian Lüscher
(2018)
Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement
eLife 7:e39945.
https://doi.org/10.7554/eLife.39945

Share this article

https://doi.org/10.7554/eLife.39945

Further reading

    1. Neuroscience
    Jian Dong, Mian Chen ... Matthijs Verhage
    Research Article

    Dense core vesicles (DCVs) transport and release various neuropeptides and neurotrophins that control diverse brain functions, but the DCV secretory pathway remains poorly understood. Here, we tested a prediction emerging from invertebrate studies about the crucial role of the intracellular trafficking GTPase Rab10, by assessing DCV exocytosis at single-cell resolution upon acute Rab10 depletion in mature mouse hippocampal neurons, to circumvent potential confounding effects of Rab10’s established role in neurite outgrowth. We observed a significant inhibition of DCV exocytosis in Rab10-depleted neurons, whereas synaptic vesicle exocytosis was unaffected. However, rather than a direct involvement in DCV trafficking, this effect was attributed to two ER-dependent processes, ER-regulated intracellular Ca2+ dynamics, and protein synthesis. Gene Ontology analysis of differentially expressed proteins upon Rab10 depletion identified substantial alterations in synaptic and ER/ribosomal proteins, including the Ca2+ pump SERCA2. In addition, ER morphology and dynamics were altered, ER Ca2+ levels were depleted, and Ca2+ homeostasis was impaired in Rab10-depleted neurons. However, Ca2+ entry using a Ca2+ ionophore still triggered less DCV exocytosis. Instead, leucine supplementation, which enhances protein synthesis, largely rescued DCV exocytosis deficiency. We conclude that Rab10 is required for neuropeptide release by maintaining Ca2+ dynamics and regulating protein synthesis. Furthermore, DCV exocytosis appeared more dependent on (acute) protein synthesis than synaptic vesicle exocytosis.

    1. Neuroscience
    Brian C Ruyle, Sarah Masud ... Jose A Morón
    Research Article

    Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.