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Dose-dependent effects of esketamine on brain activity in awake mice: A BOLD phMRI study.

Kyrsten Kawazoe, Ryan McGlynn, Wilder Felix, Raquel Sevilla, Siyang Liao, Praveen P Kulkarni, Craig F. Ferris

Pharmacology Research & Perspectives December 1, 2022 DOI: 10.1002/prp2.1035 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Preclinical dose-response imaging study Peer reviewed
Population Awake mice
Intervention Esketamine
Dose 1.0, 3.3, or 10 mg/kg I.P.
Duration 10 min post-treatment imaging
Measures blood oxygenation level dependent (BOLD) imaging
Topics Depression Ketamine Esketamine
Keywords Hippocampus Prosencephalon Animals Humans Mice Magnetic resonance imaging Nmda Prefrontal cortex Phmri
Key points Esketamine did not produce the anticipated dose-dependent increase in brain activity; instead, 1.0 mg/kg produced the greatest increases in positive BOLD signal in forebrain and hippocampal areas, while many regions showed dose-dependent decreases and a U-shaped profile across doses. The authors suggest the sensitivity to the lowest dose may relate to imaging in fully awake mice and esketamine's greater NMDAR affinity.

Abstract

Pharmacological magnetic resonance imaging (phMRI) is a noninvasive method used to evaluate neural circuitry involved in the behavioral effects of drugs like ketamine, independent of their specific biochemical mechanism. The study was designed to evaluate the immediate effect of esketamine, the S-isomer of (±) ketamine on brain activity in awake mice using blood oxygenation level dependent (BOLD) imaging. It was hypothesized the prefrontal cortex, hippocampus, and brain areas associated with reward and motivation would show a dose-dependent increase in brain activity. Mice were given vehicle, 1.0, 3.3, or 10 mg/kg esketamine I.P. and imaged for 10 min post-treatment. Data for each treatment were registered to a 3D MRI mouse brain atlas providing site-specific information on 134 different brain areas. There was a global change in brain activity for both positive and negative BOLD signal affecting over 50 brain areas. Many areas showed a dose-dependent decrease in positive BOLD signal, for example, cortex, hippocampus, and thalamus. The most common profile when comparing the three doses was a U-shape with the 3.3 dose having the lowest change in signal. At 1.0 mg/kg there was a significant increase in positive BOLD in forebrain areas and hippocampus. The anticipated dose-dependent increase in BOLD was not realized; instead, the lowest dose of 1.0 mg/kg had the greatest effect on brain activity. The prefrontal cortex and hippocampus were significantly activated corroborating previous imaging studies in humans and animals. The unexpected sensitivity to the 1.0 mg/kg dose of esketamine could be explained by imaging in fully awake mice without the confound of anesthesia and/or its greater affinity for the N-methyl-d-aspartate receptor (NMDAR) receptor than (±) ketamine.

Comparable studies

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

Study Year Design Participants
S-Ketamine Rapidly Reverses Synaptic and Vascular Deficits of Hippocampus in Genetic Animal Model of Depression Flinders Sensitive Line and Flinders Resistant Line rats 2016 Preclinical experimental study in a genetic rat model
Low-dose S-ketamine exerts antidepressant-like effects via enhanced hippocampal synaptic plasticity in postpartum depression rats. Rat model of postpartum depression induced by reproductive hormone withdrawal 2022 Animal study
Antidepressant effects of esketamine via the BDNF/AKT/mTOR pathway in mice with postpartum depression and their offspring. Mice with postpartum depression and their offspring 2024 Animal study
Electroconvulsive therapy combined with esketamine improved depression through PI3K/AKT/GLT-1 pathway. Human patients with severe depression and a rat model of depression 2025 Randomized controlled trial and animal study n = 12
S-ketamine Alleviates Neuroinflammation and Attenuates Lipopolysaccharide-Induced Depression Via Targeting SIRT2. Lipopolysaccharide (LPS)-induced mouse model 2025 Animal study with in vitro and in vivo experiments

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