Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents
Open accessAbstract
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.
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In cLH rats, naltrexone blocked the antidepressant-like effects of ketamine in the forced swim test but had no effect on immobility when given alone.
“Whereas naltrexone blocked the antidepressant-like effects of ketamine in the forced swim test, it had no impact on immobility on its own.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Klein et al., 2020
Morphine at 10 mg/kg subcutaneously did not produce the same reduction in immobility as ketamine in the forced swim test.
“morphine (10 mg/kg s.c.) was administered prior to the forced swim test but did not produce the same reduction in immobility as ketamine.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Klein et al., 2020
In congenitally learned helpless (cLH) rats, Ca2+ signaling was increased in the lateral habenula (LHb) relative to wild-type rats.
“a study using congenitally learned helpless (cLH) rats observed increased Ca2+ signaling in the lateral habenula (LHb), a brain region involved in negative affective regulation and implicated in depression, relative to WT rats (Klein et al., 2020).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Klein et al., 2020
Animal and human evidence indicates the opioid system is required-though not enough by itself-for ketamine's antidepressant action.
“For instance, preclinical and clinical studies suggest that the opioid system is necessary (although not sufficient) for ketamine’s antidepressant effects, raising possible concerns about addiction and abuse potential [117, 118].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [117]
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- Authors
- Klein, M. E., Chandra, J., Sheriff, S., & Malinow, R.
- Affiliations
- UC San Diego Health System (US)
- Corresponding author
- Klein, Matthew E.
- Malinow, Roberto
- ORCID
- Malinow, Roberto
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-01-15
- Volume
- 117
- Issue
- 5
- Pages
- 2656-2662
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7007545
- OpenAlex
- W3000480376
- Cited by
- 156
- References
- 69
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 26 · 2023: 26 · 2022: 24 · 2021: 22 · 2020: 17
- FWCI
- 13.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (R01MH091119, R25MH101072)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- ketamine, antidepressant effects, opioid system, opioid receptors, NMDA receptor, lateral habenula, depression-like behavior, suicidal behavior
- MeSH terms
- Animals, Antidepressive Agents, Depression, Disease Models, Animal, Humans, Ketamine, Male, Narcotic Antagonists, Receptors, Opioid, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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