Serotonin Reuptake Inhibition Reduces NMDAR-Associated Reward Liability Without Compromising Rapid Antidepressant Efficacy
- 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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.
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BibTeX
@misc{pan2026serotonin,
title = {{Serotonin Reuptake Inhibition Reduces NMDAR-Associated Reward Liability Without Compromising Rapid Antidepressant Efficacy}},
author = {L. Pan and G. Wang and J. Ji and Y. Cai and Y. Pang and Y. Chen and Q. Lu and X. Tang and Z. Hu and B. Zheng and Y. Xiang and Q. Hou and K. Nie and j. zhao and T. Hu and Y. He and Y. Zhang and V. Shen and W. Zhu and H. A. Aisa and G. Tian and J. Shen},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.01.763059},
url = {https://www.biorxiv.org/content/10.64898/2026.11.01.763059v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Serotonin Reuptake Inhibition Reduces NMDAR-Associated Reward Liability Without Compromising Rapid Antidepressant Efficacy
AU - L. Pan
AU - G. Wang
AU - J. Ji
AU - Y. Cai
AU - Y. Pang
AU - Y. Chen
AU - Q. Lu
AU - X. Tang
AU - Z. Hu
AU - B. Zheng
AU - Y. Xiang
AU - Q. Hou
AU - K. Nie
AU - j. zhao
AU - T. Hu
AU - Y. He
AU - Y. Zhang
AU - V. Shen
AU - W. Zhu
AU - H. A. Aisa
AU - G. Tian
AU - J. Shen
PY - 2026
DA - 2026/11/01
PB - bioRxiv
DO - 10.64898/2026.11.01.763059
UR - https://www.biorxiv.org/content/10.64898/2026.11.01.763059v1
AB - 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.
ER -