Esketamine represents a novel approach to mood disorder treatment, acting through mechanisms distinct from traditional monoaminergic antidepressants by targeting N-methyl-D-aspartate receptors (NMDARs). However, its pharmacological profile is complex, given its relatively low affinity for NMDARs and additional interactions with other targets, including opioid receptors. The precise mechanisms underlying its antidepressant effects—and its potential for misuse—remain under debate.

The dopamine system lies at the intersection of mood regulation and reward processing; therefore, we investigated esketamine’s impact on neurotransmitter dynamics within the mesolimbic dopamine pathway in mice. Our findings reveal multifaceted effects: esketamine increased locomotor activity and elevated extracellular dopamine tone, while simultaneously reducing glutamatergic activity. In contrast, it decreased the frequency of spontaneous dopamine release and blunted reward-evoked dopamine signals, resulting in reduced operant responding in a sucrose self-administration task.

To further dissect these effects, we combined optogenetic and electrical stimulation techniques to probe in vivo dopamine release and uptake dynamics. Our results indicate that esketamine’s modulation of dopamine transmission depends on glutamate release and is mediated, in part, by opioid receptor activity. These findings highlight a complex, circuit- and state-dependent interplay between neurotransmitter systems.

Clinically, this work underscores the dual-edged nature of esketamine therapy: while dopaminergic modulation may contribute to its therapeutic efficacy, the same mechanisms could underlie its potential for misuse. This emphasizes the need for careful patient monitoring and further investigation to delineate its therapeutic boundaries and mitigate associated risks.

More information:

• https://www.ub.edu/neuropharmpain/node/375