Desloratadine Rescues Schizophrenia-like Phenotypes by Inhibiting the Pathogenic 5-HT2AR-PI3K/AKT/mTOR Signaling Axis.

Authors

Yuhan Yao, Weiliang Zhao, Junyang Chen, Shentong Wang, Zhiyao Song, Lin Sun, Yubo Hu, Longyun Li

Published in

Molecular neurobiology. Volume 63. Issue 1. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

The 5-HT2A receptor (5-HT2AR) is a validated target in schizophrenia (SCZ); however, the therapeutic potential of repurposed drugs targeting this pathway remains underexplored. Here, we show that the antihistamine desloratadine (DLT) robustly ameliorates a full spectrum of SCZ-like behavioral deficits in an MK-801-induced male mouse model. Single-nucleus RNA sequencing (snRNA-seq) analysis revealed 5-HT2AR expression specifically within neuronal populations of the medial prefrontal cortex (mPFC). Mechanistically, these behavioral impairments were associated with a specific upregulation of 5-HT2AR in mPFC neurons-a molecular pathology reversed by DLT. Targeted overexpression of 5-HT2AR in mPFC neurons was sufficient to recapitulate the SCZ-like phenotypes, which are rescued by DLT, establishing a causal role for this receptor in disease pathology. Through integrated transcriptomic and biochemical analyses, we identified the PI3K/AKT/mTOR pathway as a key downstream effector of 5-HT2AR. We demonstrated that 5-HT2AR-mediated activation of this pathway drives neuroinflammation, apoptosis, and long-term potentiation impairments-effects that were effectively blocked by DLT. In a definitive pharmacological reversal experiment, activation of AKT with SC79 completely abrogated DLT's therapeutic efficacy, both behaviorally and molecularly. Collectively, our findings reveal that DLT exerts its therapeutic effects by suppressing a pathogenic feed-forward loop, wherein 5-HT2AR activates the PI3K/AKT/mTOR pathway, which may, in turn, sustain its own aberrant expression. This study provides a compelling rationale for repurposing desloratadine for SCZ and validates the 5-HT2AR-PI3K/AKT/mTOR signaling axis as a pivotal, druggable target for therapeutic intervention.

PMID:
42340538
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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