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Repeated ketamine treatment induces sex-specific behavioral and neurochemical effects in mice.

Connor Thelen, Jonathon Sens, Joseph Mauch, Radhika Pandit, Pothitos M Pitychoutis

Behavioural Brain Research October 1, 2016 DOI: 10.1016/j.bbr.2016.06.041 (opens in new tab)

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AI-extracted from the abstract
Characteristics Preclinical experimental study Peer reviewed
Population Male and female C57BL/6J mice
Intervention Ketamine
Dose 10 mg/kg
Duration 21 days
Measures open field test, forced swim test (FST)
Topics Depression Ketamine Serotonin Esketamine
Keywords 5-hiaa 5-hydroxy-indoleacetic acid Adrs Anova Antidepressant Drn Eaa Fst Gender Hnk N-methyl-d-aspartate Nmda Oft Pfc Snare Syx Stress Adverse drug reactions Analysis of variance Dorsal raphe nucleus Forced swim test Hippocampus Hydroxynorketamine Open field test Prefrontal cortex Serotonin 5-hydroxytryptamine Syntaxin-i Vehicle
Key findings Repeated ketamine treatment (10 mg/kg for 21 days) induced antidepressant-like effects in male mice but anxiety-like and depressive-like effects in female mice, with sustained sex-differentiated neurochemical and molecular changes in the hippocampus. The authors argue these opposite behavioral effects have implications for the sex-oriented use of ketamine in experimental and clinical settings.

Abstract

One of the most striking discoveries in the treatment of major depression was the finding that infusion of a single sub-anesthetic dose of ketamine induces rapid and sustained antidepressant effects in treatment-resistant depressed patients. However, ketamine's antidepressant-like actions are transient and can only be sustained by repeated drug treatment. Despite the fact that women experience major depression at roughly twice the rate of men, research regarding the neurobiological antidepressant-relevant effects of ketamine has focused almost exclusively on the male sex. Importantly, knowledge regarding the sex-differentiated effects, the frequency and the dose on which repeated ketamine administration stops being beneficial, is limited. In the current study, we investigated the behavioral, neurochemical and synaptic molecular effects of repeated ketamine treatment (10mg/kg; 21days) in male and female C57BL/6J mice. We report that ketamine induced beneficial antidepressant-like effects in male mice, but induced both anxiety-like (i.e., decreased time spent in the center of the open field arena) and depressive-like effects (i.e., enhanced immobility duration in the forced swim test; FST) in their female counterparts. Moreover, repeated ketamine treatment induced sustained sex-differentiated neurochemical and molecular effects, as it enhanced hippocampal synapsin protein levels and serotonin turnover in males, but attenuated glutamate and aspartate levels in female mice. Taken together, our findings indicate that repeated ketamine treatment induces opposite behavioral effects in male and female mice, and thus, present data have far-reaching implications for the sex-oriented use of ketamine in both experimental and clinical research settings.

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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