Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects.

Gilda Neves,Stela M.K Rates,Andresa H Betti,Camila B Antonio,Milene Borsoi,Mariana A Pranke

doi:10.1590/0001-3765201720160844

Abstract

Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

Highlights

Immobility time in the forced swimming was first described by Porsolt et al (1977) as behavioral despair and originated one of the most recognized and useful animal tasks for screening potential antidepressant drugs
Animals treated with vehicle (StudentNewman-Keuls post-hoc test, p < 0.001) and ketamine 45 mg/kg (Student-Newman-Keuls post-hoc test, p = 0.040) presented an increase in the immobility time between the first and second swimming session, which was not shown in the animals treated with ketamine 30 mg/kg (StudentNewman-Keuls post-hoc test, p = 0.487) (Figure 2)
In this work we demonstrated that repeated treatment with ketamine (30 mg/kg/day i.p. for 14 days) induced a decrease in the immobility time of mice exposed to forced swim and that this effect is not long lasting, since it is absent just three days after treatment interruption

Summary

Introduction

Immobility time in the forced swimming was first described by Porsolt et al (1977) as behavioral despair and originated one of the most recognized and useful animal tasks for screening potential antidepressant drugs. In addition to its association with depressive symptoms, an increase in immobility time has been considered a successful strategy for dealing with stress. It has been contradict this successful strategy theory. One of the most studied pharmacological animal models of schizophrenia uses N-methyl-D-aspartate receptor (NMDAR) noncompetitive antagonists administration to rodents. Schizophrenic patients treated with this drug present an exacerbation of psychosis (Lahti et al 1995). These and several other evidence support the proposition of the hypoglutamatergic hypothesis of schizophrenia and the use of NMDAR antagonists to model this psychiatric disorder in animals

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Conclusion