Serotonin Reuptake Inhibition Reduces NMDAR-Associated Reward Liability Without Compromising Rapid Antidepressant Efficacy
Libiao Pan, Guan Wang, Jing Ji, Yuting Cai, Yingting Pang, Yanmei Chen, Qiaohui Lu, Xuhua Tang, Zhengtao Hu, Baiyang Zheng, Yangyang Xiang, Qiongqiong Hou, Ke Nie, Jiangyu Zhao, Tianwen Hu, Yang He, Yan Zhang, Vivien Shen, Weiliang Zhu, Haji Akber Aisa, Guanghui Tian, Jingshan Shen
bioRxiv (Cold Spring Harbor Laboratory) November 9, 2026 preprint DOI: 10.64898/2026.11.01.763059 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study |
|---|---|
| Population | Chronic stress models of depression (preclinical) |
| Interventions | S-ketamine escitalopram VV147 |
| Topics | Serotonin |
| Key points | The authors report that escitalopram attenuates S-ketamine-induced dopamine release in the nucleus accumbens, and that a newly designed compound, VV147, which combines SERT inhibition with NMDAR antagonism, did not increase nucleus accumbens dopamine signaling while retaining rapid antidepressant effects in chronic stress models. They suggest a potential dissociation between rapid antidepressant efficacy and acute dopamine activation. |
Abstract
Ketamine has changed the treatment landscape for depression by providing rapid antidepressant effects, yet its clinical utility remains limited by psychotomimetic effects and abuse potential. It remains unclear whether rapid antidepressant efficacy can be dissociated from mesolimbic dopamine activation and its associated reward-related effects. Here, we show that the serotonin reuptake inhibitor escitalopram, by enhancing serotonergic signaling, attenuates S-ketamine-induced dopamine (DA) release in the nucleus accumbens (NAc). Inspired by this finding, we designed and evaluated VV147 by incorporating SERT inhibition into NMDAR antagonism to reduce the reward-related liability of NMDAR blockade. Unlike S-ketamine, VV147 did not increase NAc dopamine signaling but retained rapid antidepressant effects in chronic stress models of depression. Together, these findings suggest a potential dissociation between rapid antidepressant efficacy and acute dopamine activation, providing a possible strategy for developing rapid-acting antidepressants with reduced dopamine-related reward effects.
Comparable studies
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| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 11
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders Molecular Psychiatry October 3, 2017
- Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression The Journal of Clinical Psychiatry September 2, 2014
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
- Ketamine: Mechanisms and Relevance to Treatment of Depression. Annual Review of Medicine September 20, 2023
and 6 more in the library