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The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (R)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC

Agnieszka Pałucha-Poniewiera, B. Bobula, Anna Rafało-Ulińska

Pharmaceuticals February 1, 2023 DOI: 10.3390/ph16020288 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Preclinical study Peer reviewed
Population Mice (CUMS model of depression)
Intervention (R)-ketamine
Duration Single administration
Topics Depression Esketamine Ketamine
Key points A single administration of mixRL reversed CUMS-induced memory deficits and depression-like effects, and restored synaptic plasticity in the prefrontal cortex.

Abstract

(S)-Ketamine is the first rapid-acting antidepressant drug (RAAD) introduced for the treatment of depression. However, research is still being carried out on the search for further RAADs that will be not only effective but also safe to use. Recent data have indicated that the combined administration of (R)-ketamine and the mGlu2/3 receptor antagonist LY341495 (mixRL) induces rapid and sustained effects in the chronic unpredictable mild stress (CUMS) model of depression in mice, and the use of this drug combination is associated with a low risk of undesirable effects. Considering the possible influence of stress on cortical plasticity and, on the other hand, the role of this plasticity in the mechanism of action of ketamine, we decided to investigate whether mixed RL affects synaptic plasticity in the prefrontal cortex (PFC) in the CUMS model of depression using electrophysiological techniques and explore whether these effects are related to memory impairments. Using behavioral methods, we found that a single administration of mixRL reversed CUMS-induced PFC-dependent memory deficits and alleviated depression-like effects induced by CUMS. In turn, electrophysiological experiments indicated that the amplitude of field potentials as well as paired-pulse responses in CUMS mice were increased, and mixRL was found to reverse these effects. Additionally, the magnitude of long-term potentiation (LTP) was reduced in CUMS mice, and mixRL was shown to restore this parameter. In summary, mixRL appeared to exert its antidepressant effects and cognitive enhancing effects in a mouse model of depression, at least in part, by mechanisms involving modulation of glutamatergic transmission and LTP in the PFC.

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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