L-tetrahydropalmatine attenuates ketamine reward effect via modulating the miR-27a-3p/MAP2K4 axis.
Yan Du, Xing-Cui Gao, Qing Ma, Bei Li, Yanting Chen, Hong-Liang Su, Li Du, Tai-Gang Liang
Frontiers in Genetics 2026 DOI: 10.3389/fgene.2026.1701742 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats and PC12 cells |
| Intervention | Levo-tetrahydropalmatine (l-THP) |
| Topics | Esketamine Ketamine |
| Keywords | Bdnf-trkb L-tetrahydropalmatine Map2k4 Mir-27a-3p Ketamine reward effect |
| Key findings | l-THP attenuates ketamine reward effect by modulating the BDNF/TrkB pathway and the miR-27a-3p/MAP2K4 axis. |
Abstract
Ketamine (KET) addiction has already been a serious problem all over the world, which could induce neurological and psychological harm. Levo-tetrahydropalmatine (l-THP), a major alkaloid extracted from the Chinese medicinal plants Corydalis and Stephania, has been shown to attenuate ketamine (KET) induced conditioned place preference (CPP) in rats. Nevertheless, the precise mechanism remains unknown, and further research is necessary. This study aimed to investigate the role of the brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signaling pathway and microRNAs (miRNAs) in the modulatory effects of l-THP on KET reward effect. A rat CPP model and PC12 cell addiction model were developed. Next-generation high-throughput miRNA sequencing was utilized to identify candidate miRNAs. Behavioral assessments, real-time PCR, Western blotting, and cell transfection studies were conducted to clarify the impact of the selected miRNAs and the mechanism of l-THP intervention on KET reward effect. l-THP effectively attenuated KET-induced CPP and activated key proteins in the BDNF/TrkB signaling pathway. In addition, l-THP reversed the increased expression of miR-27a-3p in KET-abused rats and PC12 cells. Furthermore, inhibition of miR-27a-3p expression using an miR-27a-3p inhibitor in PC12 cells resulted in increased mitogen-activated protein kinase 4 (MAP2K4) expression, indicating that MAP2K4 is a potential functional target of miR-27a-3p in vitro. Our findings demonstrate that l-THP attenuates KET reward effect by modulating the BDNF/TrkB pathway and the miR-27a-3p/MAP2K4 axis, which may be promising targets for the intervene of KET reward effect.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 7
- Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin Neuropsychopharmacology February 24, 2020
- A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice eNeuro 2017
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
- The Pharmacological Management of Ketamine Use Disorder: A Systematic Review. Journal of Addiction Medicine
- Ketamine's Therapeutic Role in Substance Use Disorders: A Narrative Review. NeuroSci August 27, 2025
and 2 more in the library