Samuel R Krimmel1,2,3, Panos Zanos1, Polymnia Georgiou1, Luana Colloca1,4,5,6, Todd D Gould7,8,9,10. 1. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. 2. Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, USA. 3. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA. 4. Department of Pain Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA. 5. Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA. 6. Center to Advance Chronic Pain Research, University of Maryland, Baltimore, USA. 7. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. gouldlab@me.com. 8. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA. gouldlab@me.com. 9. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. gouldlab@me.com. 10. Veterans Affairs Maryland Health Care System, Baltimore, MD, 21201, USA. gouldlab@me.com.
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.
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-1mice 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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