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. Leite, Serdar M. 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 Peer reviewed DOI: 10.47626/1516-4446-2025-4301 via DOAJ
Summary
The combination of cannabidiol (CBD) and sodium nitroprusside (SNP) was effective in reducing hyperlocomotion and preventing memory deficits in both male and female rats in a ketamine model of schizophrenia. While CBD or SNP alone had limited effects, their combined use showed better outcomes, particularly in females. The study highlights distinct behavioral responses between sexes, indicating that sex may influence treatment efficacy.
Study at a glance
| Design | preclinical study |
|---|---|
| Population | Wistar rats |
| Key finding | The combination of CBD and SNP reduced hyperlocomotion and prevented memory deficits in both sexes in a ketamine model of schizophrenia. |
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.