Lurasidone sub-chronic treatment during adolescence modulates inflammatory and inositol-related metabolic pathways in the prefrontal cortex of adult male rats exposed to prenatal stress

Prenatal stress (PNS) predisposes individuals to mental disorders later in life. Adolescence is a period of heightened brain plasticity and vulnerability, when many mental disorders emerge, yet pharmacological strategies remain largely underexplored. In adult PNS rats, lurasidone (LUR) has been shown to reduce PNS-induced risk; however, its effects following adolescent administration remain unclear. To investigate the long-lasting effects of PNS and their modulation following sub-chronic LUR adolescent treatment, a whole-genome expression analysis of the prefrontal cortex (PFC) of adult male PNS rats was performed. Twelve PNS and eleven control rats were randomly assigned to receive vehicle or LUR from postnatal day (PND) 35 to 49 and sacrificed at PND 50. Partek Genomics Suite and Ingenuity Pathway Analysis were used for differential expression and pathway analyses. Within the PFC, PNS induced an upregulation of pathways involved in environmental information processing and in immune system-related pathways, which was reduced after LUR, as observed by IL-8 signaling (z-scores before: 1.34 and after LUR: −2.65). In parallel, LUR administration itself modulated Inositol-related metabolic pathways. Overall, these findings suggest that LUR adolescent treatment may counteract some PNS-induced alterations, supporting adolescence as a critical window for early preventive strategies with translational relevance for stress-related neuropsychiatric disorders.