Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia

Kandratavicius, Ludmyla; Balista, Priscila Alves; Wolf, Daniele C.; Abrão, João; Évora, Paulo Roberto Barbosa; Rodrigues, Alfredo José; Chaves, Carolina de Andrade Lima; Maia‐de‐Oliveira, João Paulo; Leite, João P.; Dursun, Serdar; Baker, Glen B.; Guimarães, Francisco Silveira; Hallak, Jaime Eduardo Cecílio

doi:10.1186/s12868-015-0149-3

Cited by 34 publications

(32 citation statements)

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“…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%

“…Similarly, it would be beneficial to use ketamine as the model of schizophrenia in the TUNL task because SNP has been effective in reducing other cognitive impairments in this model (Kandratavicius et al 2015;Trevlopoulou et al 2016). If SNP was able to alleviate ketamineinduced TUNL task impairments, ketamine treatment may hold greater predictive validity than MK-801 as a model of schizophrenia.…”

Section: Nitric Oxide Sodium Nitroprusside and Schizophreniamentioning

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: Rationale and Hypothesesmentioning

confidence: 99%

Section: Nitric Oxide Sodium Nitroprusside and Schizophreniamentioning

confidence: 99%

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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“…From another standpoint, it might be argued that the absence of effect of SNP could be due to the interval of 24 hours between its administration and the behavioral evaluations. Nevertheless, previous studies have demonstrated the effects of SNP on improving the long‐term memory deficit induced by a NMDA antagonist 48 hours after its administration, and a decrease in hyperlocomotion induced by a NMDA antagonist 1 week later the administration of SNP …”

Section: Discussionmentioning

confidence: 97%

“…SNP's antipsychotic profile was first suggested by preclinical studies—for review, see . In animal models using behavioral alterations induced by NMDA antagonists, SNP was able to attenuate hyperlocomotion, short‐ and long‐term object recognition memory and social interaction deficits . In addition, the deficit in prepulse inhibition of startle induced by a dopamine agonist is also improved by SNP .…”

Section: Discussionmentioning

confidence: 99%

Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia‐related behaviors in an animal model: The SHR strain

et al. 2018

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“…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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Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia

Cited by 34 publications

References 55 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

Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia‐related behaviors in an animal model: The SHR strain

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

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