Repeated ketamine exposure induces psychotic-like behaviors in mice via DRD1-mediated phosphorylation of p-Thr34 DARPP-32 and p-Ser10 histone H3.

ABSTRACT: Psychotic disorders frequently result from repeated ketamine exposure, yet the underlying mechanisms remain elusive. We propose that repeated exposure to ketamine may induce psychotic-like behaviors via DRD1-mediated nuclear signaling pathways. Our investigation focused on phosphorylated DARPP-32 at Thr34, Thr75, and Ser97, alongside transcriptome profiling in both cell and mouse models. We found that DRD1 antagonist mitigated ketamine-induced psychotic-like behaviors and cognitive deficits, whereas DRD1 agonist partially replicated ketamine-like symptoms. In cellular models, ketamine elevated p-Thr34 DARPP-32 levels and facilitated its nuclear accumulation through PKA, while promoting Ser10 H3 phosphorylation by inhibiting PP1 activity. Phosphorylation at Thr75 and Thr97 inhibited p-Thr34

SUBMITTER: Lv P 

PROVIDER: S-EPMC12644134 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature