The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors.
Molecular psychiatry February 19, 2025 Arianna Rizzo, Maria Zelai Garçon-Poca, Amelie Essmann et al. 14 citations
Esketamine, a new antidepressant, works through a complex interaction with brain chemicals rather than a single target. In mice, esketamine increased movement and raised overall dopamine levels by slowing dopamine removal, not by boosting its release. It also reduced glutamate activity. However, it decreased spontaneous dopamine release events and blunted reward-triggered dopamine release, which lowered the mice's motivation to work for rewards. Some of these dopamine effects were partially blocked by naloxone, an opioid blocker, and depended on glutamate input. The findings suggest esketamine's effects on brain chemistry vary by brain circuit and behavioral state.