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Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor.

Kinga Sałat, Agata Siwek, G. Starowicz, Tadeusz Librowski, Gabriel Nowak, Urszula Drabik, R. Gajdosz, Piotr Popik

Neuropharmacology December 1, 2015 DOI: 10.1016/j.neuropharm.2015.07.037 (opens in new tab)

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Characteristics Preclinical experimental study Peer reviewed
Population Mice
Interventions Ketamine Norketamine Dehydronorketamine
Dose 10 μM (binding assays); 10 and 50 mg/kg (ketamine and norketamine, IP); 5-50 mg/kg (oral ketamine)
Duration Assessed at 30 min, 3 days, and 7 days post administration
Measures [3H]MK-801 binding, forced swim test
Topics Esketamine Ketamine
Key findings Ketamine and norketamine, but not dehydronorketamine, acutely reduced immobility in the mouse forced swim test, with minimum effective doses of 10 and 50 mg/kg; the effect was absent at 3 and 7 days and after oral ketamine. The authors attribute this antidepressant-like effect to NMDA receptor inhibition.

Abstract

Ketamine produces rapid and long-lasting antidepressant effects in patients. The involvement of ketamine metabolites in these actions has been proposed. The effects of ketamine and its metabolites norketamine and dehydronorketamine on ligand binding to 80 receptors, ion channels and transporters was investigated at a single concentration of 10 μM. The affinities of all three compounds were then assessed at NMDA receptors using [3H]MK-801 binding. The dose-response relationships of all 3 compounds in the forced swim test were also investigated in mice 30 min after IP administration. The effects of ketamine and norketamine (both 50 mg/kg) were then examined at 30 min, 3 days and 7 days post administration. Among the 80 potential targets examined, only NMDA receptors were affected with a magnitude of >50% by ketamine and norketamine at the concentration of 10 μM. The Ki values of ketamine, norketamine and dehydronorketamine at NMDA receptors were 0.119±0.01, 0.97±0.1 and 3.21±0.3 μM, respectively. Ketamine and norketamine reduced immobility with minimum effective doses (MEDs) of 10 and 50 mg/kg, respectively; dehydronorketamine did not affect immobility at doses of up to 50 mg/kg. Neither ketamine nor norketamine reduced immobility in the forced swim test 3 and 7 days following administration. Further, oral administration of ketamine (5-50 mg/kg) did not affect immobility. We demonstrate that ketamine and norketamine but not dehydronorketamine given acutely at subanesthetic doses reduced immobility in the forced swim test. These antidepressant-like effects appear attributable to NMDA receptor inhibition.

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