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. Graphical Abstract mPFC neuronal 5-HT2AR upregulation activates PI3K/AKT/mTOR signaling to drive neuroinflammation, apoptotic stress, synaptic dysfunction, and schizophrenia-like behaviors. Desloratadine attenuates these phenotypes by suppressing the pathway, and AKT activation counteracts the rescue (created using BioRender).