, Volume 237, Issue 1, pp 93–102 | Cite as

Classical conditioning of antidepressant placebo effects in mice

  • Samuel R. Krimmel
  • Panos Zanos
  • Polymnia Georgiou
  • Luana Colloca
  • Todd D. GouldEmail author
Original Investigation



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.


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.


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.


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.


Ketamine Placebo Antidepressant Classical conditioning Depression Animal model Mice Biological sex 


Funding information

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

Compliance with ethical standards

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.


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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Department of Neural and Pain SciencesUniversity of Maryland School of DentistryBaltimoreUSA
  3. 3.Program in NeuroscienceUniversity of Maryland School of MedicineBaltimoreUSA
  4. 4.Department of Pain Translational Symptom ScienceUniversity of Maryland School of NursingBaltimoreUSA
  5. 5.Department of AnesthesiologyUniversity of Maryland School of MedicineBaltimoreUSA
  6. 6.Center to Advance Chronic Pain ResearchUniversity of MarylandBaltimoreUSA
  7. 7.Department of PharmacologyUniversity of Maryland School of MedicineBaltimoreUSA
  8. 8.Department of Anatomy and NeurobiologyUniversity of Maryland School of MedicineBaltimoreUSA
  9. 9.Veterans Affairs Maryland Health Care SystemBaltimoreUSA

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