Role of PI3K/Akt axis in cognitive impact of lumateperone in schizophrenia rat model induced by ketamine

Abstract

Schizophrenia (SCZ) is a complex, debilitating mental illness marked by cognitive deficits that impair functionality and quality of life. While traditional research has focused on dopaminergic and glutamatergic abnormalities in SCZ, emerging evidence highlights the crucial role of serotonergic dysregulation. Lumateperone (LUM), a recently FDA-approved atypical antipsychotic, exhibits a distinctive multimodal pharmacological profile characterized by combined antagonism of 5-HT2Aand D2 receptors alongside serotonin reuptake inhibitory activity. This study investigated the procognitive effects of LUM mediated via 5-HT1Areceptor activation in ketamine (Ket)-induced SCZ-like rat model. To this end, Male Wistar rats were administered 5 days Ket (30 mg/kg/day, i.p.), followed by LUM (10 mg/kg/day, p.o) for 14 days. To evaluate the proposed mechanistic pathway, a selective PI3K inhibitor (15 μg/kg/day, iv) Wortmannin (WM) was administered 30 min prior to LUM. Four days before the termination, animals underwent behavioral assessments, including the open field test, novel object recognition task, social interaction, Y-maze, and Morris water maze test. LUM restored hippocampal/cortical architecture, improved Ket-induced behavioral/cognitive deficits, reduced cortical CD86/GFAP, and increased CD163 immunoreactivity. Additionally, LUM decreased SERT expression and corrected the dysregulated expression of cortical 5-HT2Aand hippocampal 5-HT1Areceptors. LUM restored hippocampal 5-HT,5-HIAA, and DA levels while amending cortical GAD67 and VGLUT1 immunoexpression. Alongside restoring PI3K/AKT/GSK-3β survival proteins and reinstating pCREB and BDNF levels. WM pre-administration nullified LUM's effects, proving the involvement of the 5-HT1A/PI3K/Akt pathway. LUM demonstrates promising procognitive potential, offering insights into its therapeutic applications for cognitive dysfunction in SCZ.