The Dopaminergic Effects of Esketamine are Mediated by a Dual Mechanism Involving Glutamate and Opioid Receptors

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 used behavioral models and in vivo fiber photometry to explore the neurochemical effects of esketamine in the nucleus accumbens of mice. Our findings demonstrated multimodal effects of esketamine on extracellular dopamine dynamics. Generally, esketamine increased dopaminergic tone while decreasing glutamatergic transmission. However, it decreased dopamine phasic activity and impaired reward-evoked dopamine release. These 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.