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The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors.

Arianna Rizzo, Maria Zelai Garçon-Poca, Amelie Essmann, Adriana Jesus Souza, Michael Michaelides, Francisco Ciruela, Jordi Bonaventura

Molecular Psychiatry February 19, 2025 DOI: 10.1038/s41380-025-02931-3 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Mice
Intervention Esketamine
Topics Esketamine
Keywords Psychopharmacology Depression treatment Brain chemistry Mental health
Citations 14
Key findings Esketamine increases overall dopamine tone by impairing clearance but reduces reward-evoked dopamine release and operant responding, effects that are partially opioid-dependent and require glutamatergic input.

Abstract

Esketamine represents a new class of drugs for treating mood disorders. Unlike traditional monoaminergic-based therapies, esketamine primarily targets N-methyl-D-aspartate receptors (NMDAR). However, esketamine is a complex drug with low affinity for NMDAR and can also bind to other targets, such as opioid receptors. Its precise mechanism of action for its antidepressant properties remains debated, as does its potential for misuse. A key component at the intersection of mood and reward processing is the dopaminergic system. In this study, we evaluated the effects of esketamine in locomotion, anxiety tests and operant responding and we used in vivo fiber photometry to explore the neurochemical effects of esketamine in the nucleus accumbens of mice. Our findings demonstrated multifaceted effects of esketamine on neurotransmitter dynamics. In freely behaving mice, esketamine increased locomotion and increased extracellular dopamine tone -by impairing dopamine clearance rather than promoting dopamine release- while decreasing glutamatergic activity. However, it decreased dopamine spontaneous release event frequency and impaired reward-evoked dopamine release, leading to a reduction in operant responding rates. These dopaminergic effects were partially, and conditionally, blocked by the opioid antagonist naloxone and required glutamatergic input. In summary, our study reveals a complex interaction between neurotransmitter systems, suggesting that the neurochemical effects of esketamine are both circuit- and state-dependent.

Comparable studies

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

Study Year Design Participants
Reduction of dopamine D2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys Conscious monkeys 2016 Experimental study
Esketamine Prevents Postoperative Emotional and Cognitive Dysfunction by Suppressing Microglial M1 Polarization and Regulating the BDNF-TrkB Pathway in Ageing Rats with Preoperative Sleep Disturbance Aged mice 2024 Animal study
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

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