Nitroprusside single-dose prevents the psychosis-like behavior induced by ketamine in rats for up to one week

Maia‐de‐Oliveira, João Paulo; Lobão-Soares, Bruno; Ramalho, Thais; Gavioli, Elaine C.; Soares, Vanessa P.; Teixeira, Leslie; Baker, Glen B.; Dursun, Serdar; Hallak, Jaime Eduardo Cecílio

doi:10.1016/j.schres.2014.12.035

Cited by 25 publications

(35 citation statements)

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“…These measurements are believed to be rodent analogues to aspects of the positive, negative and cognitive symptoms of schizophrenia (Maiade-Oliveira et al 2015b;Trevlopoulou et al 2016). Rodent effects were observed up to one week after administration, further supporting the long-term efficacy of SNP (Maia-de-Oliveira et al 2015b). Although the mechanism underlying these changes are not fully understood, this evidence supports SNP as a viable treatment to alleviate the symptoms of schizophrenia and improve patient quality of life.…”

Section: Introductionmentioning

confidence: 86%

“…Further, SNP has the potential to prevent and rescue ketamine-induced impairments in cognitive tasks (Kandratavicius et al 2015;Maia-de-Oliveira et al 2015b). Therefore, it is hypothesized that, similar to ketamine studies, acute MK-801-induced impairments on the TUNL task will be reversed when rats are pre-or co-treated with SNP.…”

Section: Rationale and Hypothesesmentioning

confidence: 99%

“…Previous studies have examined the potential of SNP to prevent the cognitive impairments observed in NMDA dysfunction models of schizophrenia (Maia-de-Oliveira et al 2015b). A previously published experiment using MK-801 in TUNL found that the 0.05 mg/kg dose of MK-801 was sufficient to reduce performance compared to saline, as higher doses led to high omission rates (Kumar et al 2015a).…”

Section: Snp Does Not Prevent Mk-801-induced Impairments In the Tunl mentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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The cognitive symptoms observed in schizophrenia are highly prevalent and predictive of patient functional outcome but are not usually alleviated by conventional antipsychotics. In a recent pilot study, sodium nitroprusside (SNP), a nitric oxide donor, was identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.Adjunctive SNP has also been reported to decrease the positive and negative symptoms experienced by patients for weeks following a single administration. The mechanisms underlying these changes and the areas of cognition affected remain largely unknown.Therefore, it is of interest to examine the effects of SNP using a rodent model of schizophrenia that has demonstrated predictive validity. The aim of the present experiment was to explore the effects of SNP on the acute MK-801 rodent model of schizophrenia using a highly translatable task in order to establish its validity. Working memory and pattern separation were measured using the trial-unique, delayed nonmatching-to-location (TUNL) task in touchscreen-equipped operant conditioning chambers. Acute MK-801 administration 25 minutes prior to task initiation impaired both areas of cognition. When SNP and MK-801 were administered within 5 minutes of each other, no interaction was observed. Interestingly, SNP improved performance on trials with difficult to discriminate patterns (p=0.058). Previous rodent studies using the ketamine model of schizophrenia and the novel object preference task observed a preventative effect of SNP administration. When we administered SNP nearly 4 hours prior to MK-801, no cognitive improvements were observed. Our results suggest that SNP may have intrinsic cognitive enhancing properties but is not capable of reducing MK-801-induced working memory and pattern separation impairments in the TUNL task. This study failed to mirror the results of the human pilot study that observed improved working memory following SNP administration.iii Further, it did not replicate previous animal studies using ketamine. Ultimately, the findings suggest that the effects of MK-801 in the TUNL task may not hold the predictive validity needed for its use in the study of SNP. In order to advance the understanding of SNP, future studies should investigate other translatable paradigms to establish validity. iv ACKNOWLDGEMENTSFirst and foremost, I would like to thank my supervisor Dr. John Howland, for his guidance and encouragement over the past three years. He believed in my abilities before I had proven them to myself and pushed me to be the best scientist and student I could be. John has provided me with countless opportunities to grow as a researcher and selflessly helped me make decisions about my future. I would not be where I am today without him and will always be grateful to have had such an incredible mentor in my life.I would like to thank my committee members, Dr.

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Section: Introductionmentioning

confidence: 86%

Section: Rationale and Hypothesesmentioning

confidence: 99%

Section: Snp Does Not Prevent Mk-801-induced Impairments In the Tunl mentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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“…Phencyclidine (PCP) and ketamine are widely used in animal models of schizophrenia, and both drugs act by blocking the action of glutamate on N-methyl-D-aspartate (NMDA) receptors 3,4 . These receptors mediate the production of neuronal nitric oxide (NO) and, therefore, the hypothesis was raised that schizophrenia could be related to decreased levels of NO in the brain.…”

Section: Introductionmentioning

confidence: 99%

“…They reported that pretreatment with SNP prevented behavioral changes in the animals that are commonly associated with positive symptoms in humans, such as hyperactivity and stereotypy, and that this effect lasted for up to one week 3,5 .…”

Section: Introductionmentioning

confidence: 99%

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine – A translational double-blind study

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Maia‐de‐Oliveira

Kandratavicius

et al. 2017

Arch. Clin. Psychiatry (São Paulo)

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Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38) were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min). First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

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The nitric oxide donor sodium nitroprusside attenuates recognition memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats

2015

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Nitroprusside single-dose prevents the psychosis-like behavior induced by ketamine in rats for up to one week

Cited by 25 publications

References 36 publications

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine – A translational double-blind study

The nitric oxide donor sodium nitroprusside attenuates recognition memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats

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