Prophylactic efficacy of cannabidiol and sodium nitroprusside in a ketamine model of schizophrenia: sex-dependent effects on positive-like and cognitive impairments
Daniel B.a. Prado, Matheus T. Rossignoli, Rafael N. Ruggiero, José E.p. Santos, João P C Leite, Serdar Dursun, Leman H. Dursun, Antonio W. Zuardi, Rafael G. Dos Santos, Vanessa C. Abilio, João Abrão, José A. Crippa, Gleiciane G. Avelar, Jaime E. C. Hallak, Isabella C.s. Dias
Brazilian Journal of Psychiatry June 16, 2026 DOI: 10.47626/1516-4446-2025-4301 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Wistar rats |
| Interventions | Cannabidiol Sodium nitroprusside |
| Duration | Pretreatment on postnatal days 12-32, 10-day washout, then behavioral testing |
| Topics | CBD Ketamine Esketamine |
| Keywords | Schizophrenia Sex Sodium nitroprusside |
| Key points | The combination of cannabidiol and sodium nitroprusside reduced hyperlocomotion and prevented novel object recognition deficits in both sexes in a ketamine rodent model of schizophrenia, with superior prophylactic effects in females. |
Abstract
Objective: Current treatments for schizophrenia (SZ) are often not effective 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, SZ-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 SZ model, suggesting a promising therapeutic strategy.