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Acute administration of ketamine reverses the inhibition of mitochondrial respiratory chain induced by chronic mild stress.

Gislaine T Rezin, Cinara L Gonçalves, Juliana F Daufenbach, Daiane B Fraga, Patricia M Santos, Gabriela K Ferreira, Fernanda V Hermani, Clarissa M Comim, João Quevedo, Emilio L Streck

Brain Research Bulletin August 14, 2009 DOI: 10.1016/j.brainresbull.2009.03.010 (opens in new tab)

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Study at a glance

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Characteristics Animal experimental study Peer reviewed
Population Rats subjected to chronic mild stress as an animal model of depression
Intervention Ketamine
Dose 15 mg/kg
Duration 40 days of chronic mild stress, with acute ketamine administration
Topics Esketamine Ketamine
Key findings Chronic mild stress inhibited mitochondrial respiratory chain complexes I, III, and IV in rat cerebral cortex and cerebellum, and a single 15 mg/kg dose of ketamine reversed this inhibition along with stress-induced adrenal gland enlargement. Ketamine did not reverse the stress-induced decrease in sweet-food intake, so the behavioral deficit persisted despite the biochemical and physiological changes.

Abstract

Modulation and dysfunction of the glutamatergic system seems to be involved in depression. Recently a renewed interest in the glutamatergic system as a treatment option for major depression emerged by the finding that the glutamate N-methyl-D-aspartate (NMDA) antagonist ketamine leads to a rapid improvement of depressive symptoms. Several works support the hypothesis that metabolism impairment is involved in the pathophysiology of depression. We have also recently reported that mitochondrial respiratory chain complexes I, III and IV were inhibited in cerebral cortex and cerebellum of rats after 40 days of chronic mild stress (CMS), which is used as an animal model of depression. Thus, we investigated whether the inhibition of these enzymes may be reversed by acute administration of ketamine (15 mg/kg). We verified that CMS decreased the intake of sweet food and ketamine was not able to reverse such effect. Adrenal gland weight was increased in stressed rats and ketamine reversed this alteration. Control group gained weight after 40 days but stressed group did not gain weight after the same period. Stressed animals gained weight after acute administration of ketamine, when compared to the body weight assessed at the beginning of the experiment. Finally, we verified that complexes I, III and IV were inhibited after CMS in cerebral cortex and cerebellum and acute administration of ketamine reversed this inhibition. Based on the present findings, we hypothesized that CMS induces inhibition of mitochondrial respiratory chain (complexes I, III and IV) and that acute administration of ketamine reverses such effect.

Comparable studies

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

Study Year Design Participants
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats 2010 Observational study
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats 1997 Dose-response study with microdialysis and behavioral testing
NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice 2016 Preclinical study
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats 1983 Experimental study
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice 2015 Experimental study

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Esketamine Ketamine Depression