Classical conditioning of antidepressant placebo effects in mice
Open accessAbstract
Introduction Placebo effects in human clinical trials for depression treatment are robust and often comparable to drug effects. Placebo effects are traditionally difficult to study in rodents due to the slow-onset action of classical antidepressant drugs. We hypothesized that the rapid antidepressant actions of ketamine would allow modeling antidepressant placebo effects in rodents.Methods Male and female CD-1 mice received either ketamine or saline injections with concomitant exposure to specific environmental conditioning stimuli, for a total of three drug/conditioning sessions each 2 weeks apart. Two weeks later, during an evocation phase, mice were exposed to the drug-paired conditioning stimuli or no conditioned stimuli followed by testing for motor stimulatory actions and antidepressant-like effects using the forced swim test. Negative (no ketamine administration at any time) and positive (acute ketamine administration prior to evocation testing) control groups were included as comparators.Results Both male and female mice exhibited increased locomotor activity following ketamine administration during the conditioning phase, which was not observed following exposure to the conditioning stimuli. Exposure to the conditioning stimuli previously paired with ketamine, similar to an acute ketamine administration, reduced immobility time in the forced swim test both 1 and 24 h after administration in male, but not female, mice.Conclusions These results represent the first evidence of antidepressant-like placebo-conditioned effects in an animal model. The developed approach can be used as a model to explore the neurobiological mechanisms of placebo effects, their possible sexually dimorphic effects, and relevance to mechanisms underlying antidepressant action.
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The leading theory holds that an intact opioid system is needed for ketamine-and perhaps placebo-to produce antidepressant effects.
“The current predominant theory according to these studies is that ketamine, and possibly the placebo effect, require a functional opioid system to achieve their antidepressant effects (Krimmel et al., 2020).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Krimmel et al., 2020
The Introduction and Discussion report antidepressant-like effects of ketamine and conditioned placebo responses, but do not say that either requires a functional opioid system. A search for “opioid” found only a reference concerning placebo analgesia, not this proposed requirement for antidepressant effects. Page numbers were not available in our copy. (LLM, conf=0.76)
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Self-citation
- Authors
- Krimmel, S. R., Zanos, P., Georgiou, P., Colloca, L., & Gould, T. D.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Gould, Todd D.
- Venue
- Psychopharmacology
- Published
- 2019-08-17
- Volume
- 237
- Issue
- 1
- Pages
- 93-102
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC6954278
- OpenAlex
- W2968879233
- Cited by
- 12
- References
- 60
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 1
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH107615)
- U.S. Department of Veterans Affairs (1I01BX004062)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- placebo effect, ketamine, classical conditioning, conditioned stimulus, forced swim test, antidepressant-like effects, locomotor activity, sex differences, depression
- MeSH terms
- Animals, Antidepressive Agents, Conditioning, Classical, Depressive Disorder, Disease Models, Animal, Female, Ketamine, Locomotion, Male, Swimming, Placebo Effect, Mice
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