Blocking dopamine D1 receptor (Drd1) activity with an antagonist reduced ketamine-induced schizophrenia-like behaviors in mice, while activating Drd1 with an agonist partly reproduced those symptoms. Transcriptome analysis of the mouse hippocampus identified changes in genes involved in the GTPase activation pathway, including Rgs4 and Gnai3. Two weeks after ketamine administration, Gnai3 mRNA expression decreased in peripheral blood and serum levels of eotaxin-2 increased. These molecular changes suggest Gnai3 and eotaxin-2 may serve as potential peripheral biomarkers for ketamine abuse. The findings demonstrate Drd1 activity's crucial role in ketamine-induced psychotic-like disorder in a mouse model.
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.
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.