The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors.
Molecular psychiatry – February 19, 2025
Source: PubMed
Summary
Groundbreaking research reveals how esketamine, a promising depression treatment, works through an intricate dance of brain chemicals. The drug affects dopamine levels in the brain's reward center through two distinct pathways - one involving glutamate and another through opioid receptors. While it increases overall dopamine levels, it actually reduces dopamine's response to rewards, explaining both its therapeutic benefits and potential drawbacks. This dual mechanism helps explain why esketamine's effects on mood and behavior are so unique.
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.