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Ketamine evokes acute behavioral effects via μ-opioid receptor expressing neurons of the central amygdala.

Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach, Daniel Ryskamp Rijsketic, Austen B Casey, Nicholas Gregory, Wesley Zhao, Tyler E. Girard, Kathryn T Mattox, Juliana S Salgado, Robert C. Malenka, Boris D. Heifets

Biological Psychiatry May 5, 2025 DOI: 10.1016/j.biopsych.2025.04.020 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Male and female wild-type mice
Interventions Ketamine naltrexone MOR-selective antagonist MK-801
Topics Depression Ketamine Esketamine
Keywords Antidepressant Central amygdala Mu opioid receptor Naltrexone Depression treatment Brain receptors Psychopharmacology Ketamine therapy Neuroscience research
Citations 11
Key findings Ketamine acts at mu opioid receptors in the central amygdala to produce acute hyperlocomotion in mice.

Abstract

Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. This mechanism may differentiate ketamine from other NMDA receptor antagonists. Animal models that reflect OR-dependent behavioral effects of ketamine may shed light on the brain regions and circuits that contribute to ketamine's antidepressant mechanism in humans. We screened male and female wild-type mice for a behavioral response to ketamine that could be reversed by OR antagonists in several assays, including locomotor activation, analgesia, and the forced swim test. Whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, was used to identify brain areas mediating ketamine / OR interactions. Region-specific pharmacological and genetic interference with μOR (MOR) signaling was used to test predictions of whole-brain imaging results in a subset of behavioral assays. Among a series of behavioral assays, only locomotor-activation was sensitive to ketamine and blocked by an MOR-selective antagonist. Locomotor activation produced by the NMDA receptor antagonist, MK-801, was not OR-dependent. Whole-brain imaging revealed cFos expression in neurons of the central amygdala (CeA) showed the greatest difference between ketamine in the presence versus absence of naltrexone. CeA neurons expressing both MOR and PKCδ were strongly activated by naltrexone, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that ketamine acts at MORs expressed in CeA neurons to produce acute hyperlocomotion.

Comparable studies

Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

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