Prophylactic efficacy of cannabidiol and sodium nitroprusside in a ketamine-model of schizophrenia: sex-dependent effects on positive-like and cognitive impairments.

Objective: Current treatments for schizophrenia (SZ) are often ineffective for all symptoms, with sex-dependent effects poorly understood. Cannabidiol (CBD) and sodium nitroprusside (SNP) have emerged as potential prophylactic options. We evaluated their efficacy in preventing positive, negative, and cognitive deficits in a ketamine (KET) rodent model of SZ in both sexes.

Methods: Wistar rats were pretreated with CBD and SNP (alone or combined) during brain development (postnatal days 12-32). After 10 days, schizophrenia-like deficits were induced via KET. Behaviors were assessed using the Open Field Test (OFT), Sucrose Preference Test (SPT), and Novel Object Recognition (NOR) test.

Results: KET induced sex-dependent effects: females showed greater hyperlocomotion and long-term NOR memory deficits, while males exhibited reduced sucrose preference and short-term NOR impairments. CBD or SNP alone had limited efficacy, but their combination reduced hyperlocomotion and prevented NOR deficits in both sexes. Multivariate analysis revealed superior prophylactic effects in females, with unsupervised clustering showing distinct behavioral phenotypes between sexes.

Conclusion: This study provides the first preclinical evidence of sex-dependent prophylactic efficacy of CBD-SNP in a schizophrenia model, suggesting a promising therapeutic strategy.