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Classical conditioning of antidepressant placebo effects in mice

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Abstract

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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Funding

This research was supported by NIH/NIMH R01-MH107615 and VA Merit Award 1I01BX004062 to TDG.

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Authors and Affiliations

  1. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Samuel R. Krimmel, Panos Zanos, Polymnia Georgiou, Luana Colloca & Todd D. Gould

  2. Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, USA

    Samuel R. Krimmel

  3. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA

    Samuel R. Krimmel

  4. Department of Pain Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA

    Luana Colloca

  5. Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Luana Colloca

  6. Center to Advance Chronic Pain Research, University of Maryland, Baltimore, USA

    Luana Colloca

  7. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA

    Todd D. Gould

  8. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Todd D. Gould

  9. Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA

    Todd D. Gould

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  1. Samuel R. Krimmel
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  2. Panos Zanos
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Corresponding author

Correspondence to Todd D. Gould.

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All experimental procedures were approved by the University of Maryland, Baltimore Animal Care and Use Committee and were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the US Government.

Conflict of interest

TDG has received research funding from Allergan, and Roche Pharmaceuticals, and consultant fees from FSV7 LLC during the preceding 3 years. LC reported having received support for Invited Lectures outside the submitted work.

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Samuel R. Krimmel and Panos Zanos have equal first author contributions.

Luana Colloca and Todd D. Gould have equal senior author contributions.

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Krimmel, S.R., Zanos, P., Georgiou, P. et al. Classical conditioning of antidepressant placebo effects in mice. Psychopharmacology 237, 93–102 (2020). https://doi.org/10.1007/s00213-019-05347-4

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