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 DOI: 10.47626/1516-4446-2025-4301 via DOAJ
Summary
AI-generated from the abstractIn a rat model of schizophrenia-like symptoms induced by ketamine, the combination of cannabidiol and sodium nitroprusside given during brain development prevented hyperactivity and memory problems in both sexes, while each drug alone had limited effects. The model produced different symptoms in males and females: females showed greater hyperactivity and long-term memory deficits, whereas males showed reduced pleasure-seeking and short-term memory impairments. The combined treatment was more effective in females, and distinct behavioral patterns were seen between sexes. This suggests that a combination of these two compounds may offer a sex-specific preventive strategy for schizophrenia symptoms.
Study at a glance
| 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 |
| Keywords | Schizophrenia Sex Sodium nitroprusside |
| Key finding | 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.