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 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.
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.