L-tetrahydropalmatine attenuates ketamine reward effect via modulating the miR-27a-3p/MAP2K4 axis.

Levo-tetrahydropalmatine (l-THP), an alkaloid from Chinese medicinal plants, reduces the rewarding effect of ketamine in rats, as measured by conditioned place preference. The compound activates the BDNF/TrkB signaling pathway and reverses increased expression of miR-27a-3p in ketamine-exposed rats and PC12 cells. Inhibiting miR-27a-3p in PC12 cells increases MAP2K4 expression, suggesting MAP2K4 is a functional target of this microRNA. These findings indicate that l-THP attenuates ketamine reward through modulation of the BDNF/TrkB pathway and the miR-27a-3p/MAP2K4 axis, which may offer targets for intervention.

Study at a glance

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.