Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
June 1, 2024
Xue Wu, Gehua Wen, Lei Yan et al.
11 citations
Ketamine, a drug originally used as an anesthetic and now commonly abused in China, can cause cognitive impairment by disrupting the brain's glymphatic system, which normally clears metabolic waste. In a mouse model of short-term ketamine administration, the drug increased expression of the 5-HT2c receptor in hippocampal astrocytes, leading to accumulation of the transcription factor ΔFosb. ΔFosb then bound to a specific DNA sequence in the regulatory region of the Aqp4 gene, suppressing Aqp4 expression and impairing glymphatic circulation, which resulted in cognitive deficits. This mechanism does not involve the Pten/Akt pathway and reveals a non-neuronal basis for ketamine-induced cognitive harm, informing clinical safety and withdrawal effectiveness.
Cell Biology and Toxicology
January 30, 2026
Jia-Yi Wei, Peng Lv, Jiayu Zhang et al.
Repeated ketamine exposure over seven days causes anxiety-like and depressive-like behaviors along with cognitive deficits in mice. The dopamine receptor DRD1 plays a key role in these effects: activating DRD1 produces anxiety-like behavior similar to ketamine and worsens ketamine's effects, while blocking DRD1 partially reduces anxiety but worsens depression. Ketamine triggers apoptosis (cell death) in HT22 cells by suppressing Akt/Gsk3β phosphorylation through DRD1. In mice, ketamine promotes neuronal apoptosis in the hippocampus and prefrontal cortex; blocking DRD1 partially reduces this apoptosis, but knocking down DRD1 in neurons unexpectedly increases both apoptosis and anxiety-like behavior.
Cell Biology and Toxicology
November 25, 2025
Peng Lv, Jiayu Zhang, Jia-Yi Wei et al.
Repeated ketamine exposure can trigger psychotic-like behaviors and cognitive deficits through a specific molecular pathway involving the dopamine receptor DRD1. The DRD1–DARPP-32–Histone H3 signaling cascade mediates transcriptional abnormalities and impairs neurogenesis in the hippocampus. Blocking DRD1 alleviated these effects, while activating it partially reproduced ketamine-like symptoms. In cellular and mouse models, ketamine increased phosphorylation of DARPP-32 at Thr34, promoting its nuclear accumulation and leading to histone H3 phosphorylation. This altered gene expression and reduced the generation of new neurons and neural stem cells in the dentate gyrus, while increasing astrocyte numbers. The findings suggest a key mechanism underlying ketamine-induced schizophrenia-like symptoms.
Neurotoxicology and Teratology
February 21, 2022
Xiaojiaoyang Li, Juanhan Yu, Xue Wu et al.
High-dose ketamine given to mice for seven consecutive days produced schizophrenia-like symptoms, including increased activity and impaired spatial learning and memory. Ketamine reduced levels of three microRNAs (miR-15a-3p, miR-15b-3p, miR-16-1-3p) in the prefrontal cortex and one (miR-16-1-3p) in the hippocampus, while increasing expression of the dopamine D1 receptor (DRD1) in those brain regions. In mouse hippocampal neurons, ketamine raised DRD1 levels in a dose-dependent way, and adding mimics of miR-15b-3p and miR-16-1-3p partially reversed this increase. A specific sequence in the DRD1 gene's regulatory region was identified as the target of these microRNAs.
Xinghua Ren, Siyi Zhang, Yongyan Yang et al.
Ketamine, an anesthetic and antidepressant, can induce delirium-like behavior in mice and increase tau protein in their blood. In cultured cells, ketamine disrupts endosome function—key organelles for tau release—by increasing endosomal markers Rab5 and Rab7, inhibiting endosome maturation, and boosting tau accumulation in endosomes and the culture medium. These findings suggest ketamine may interfere with tau trafficking, potentially contributing to neurotoxicity and delirium, warranting further research into anesthetic safety.