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Research Article

Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents

Matthew E. Klein, Joshua Chandra, Salma Sheriff, and Roberto Malinow
PNAS February 4, 2020 117 (5) 2656-2662; first published January 15, 2020 https://doi.org/10.1073/pnas.1916570117
Matthew E. Klein
aDepartment of Psychiatry, University of California San Diego (UCSD) School of Medicine, San Diego, CA 92093;bDepartment of Neurosciences, UCSD School of Medicine, San Diego, CA 92093;cSection of Neurobiology, Division of Biology, UCSD, San Diego, CA 92093
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  • For correspondence: meklein@ucsd.edu rmalinow@ucsd.edu
Joshua Chandra
bDepartment of Neurosciences, UCSD School of Medicine, San Diego, CA 92093;cSection of Neurobiology, Division of Biology, UCSD, San Diego, CA 92093
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Salma Sheriff
bDepartment of Neurosciences, UCSD School of Medicine, San Diego, CA 92093;cSection of Neurobiology, Division of Biology, UCSD, San Diego, CA 92093
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Roberto Malinow
bDepartment of Neurosciences, UCSD School of Medicine, San Diego, CA 92093;cSection of Neurobiology, Division of Biology, UCSD, San Diego, CA 92093
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  • For correspondence: meklein@ucsd.edu rmalinow@ucsd.edu
  1. Contributed by Roberto Malinow, November 29, 2019 (sent for review September 24, 2019; reviewed by Hailan Hu and Bo Li)

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Significance

Ketamine, an NMDA receptor antagonist, has generated intense excitement as a therapy for treatment-resistant depression. However, ketamine and its metabolites can act on a wide range of targets, including opioid receptors, which has raised concerns. Using behavioral and cellular assays in rodents, we find that blocking opioid function prevents the antidepressant-like effects of ketamine. However, in contrast to ketamine, administration of a µ-opioid agonist is hedonic and ineffective on anhedonia/avolition. Furthermore, ketamine’s cellular actions are both mimicked and occluded by an NMDAR antagonist but not by a µ-opioid agonist. These results suggest that ketamine does not act as a μ-opioid agonist, but functional μ-opioid receptors are permissive for the antidepressant effects of ketamine.

Abstract

Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.

  • lateral habenula
  • ketamine
  • opioid system

Footnotes

  • ↵1To whom correspondence may be addressed. Email: meklein{at}ucsd.edu or rmalinow{at}ucsd.edu.
  • Author contributions: M.E.K. and R.M. designed research; M.E.K., J.C., and S.S. performed research; M.E.K. and R.M. analyzed data; and M.E.K. and R.M. wrote the paper.

  • Reviewers: H.H., Zhejiang University; and B.L., Cold Spring Harbor Laboratory.

  • The authors declare no competing interest.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1916570117/-/DCSupplemental.

Published under the PNAS license.

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Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents
Matthew E. Klein, Joshua Chandra, Salma Sheriff, Roberto Malinow
Proceedings of the National Academy of Sciences Feb 2020, 117 (5) 2656-2662; DOI: 10.1073/pnas.1916570117

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Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents
Matthew E. Klein, Joshua Chandra, Salma Sheriff, Roberto Malinow
Proceedings of the National Academy of Sciences Feb 2020, 117 (5) 2656-2662; DOI: 10.1073/pnas.1916570117
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