Atypical antipsychotics reduce MK801-induced social deficits in RHA rats: A schizophrenia model

What is it about?

The administration of NMDA receptor (NMDAR) antagonists constitutes a widely used model that produce both positive (e.g., hyperactivity) and negative (e.g., social withdrawal) symptoms relevant for schizophrenia in rodents. These effects can be reversed with the administration of atypical (second and third generation) antipsychotics. Objectives: In this study we combined the NMDAR-antagonist model with the Roman High-Avoidance (RHA) strain, a psychogenetically selected model of schizophrenia- relevant features. We also studied whether some atypical antipsychotics drugs (clozapine, ziprasidone, and aripiprazole) would be able to attenuate or reverse the behavioural alterations induced by MK801- and whether such effects might be dependent on the rat strain. Methods: MK801 dose-response study was conducted in RHA and Roman Low Avoidance (RLA) male rats. After that, the 0.15 mg/kg MK801 dose was selected to carry out pharmacological studies versus atypical antipsychotics. Results: In the first experiment we establish that MK801 (dizocilpine), a NMDAR antagonist, produces dose-related hyperactivity and social withdrawal, which are more marked in RHA than RLA rats. The administration of the atypical antipsychotics clozapine (2.5. mg/kg) or ziprasidone (2.5 mg/kg) partially reversed orattenuated some of the social behaviour deficits and hyperactivity induced by the administration of MK801. Aripiprazole (3 mg/kg), a third-generation antipsychotic, reversed or attenuated the social preference deficit, the hyperactivity and the impairment of social latency induced by MK801. Conclusions: These results seem to be in line with previous studies with the NMDAR-antagonist model and add face and predictive validity to the RHA rat strain as a model of schizophrenia-relevant features.

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Photo by Towfiqu barbhuiya on Unsplash

Photo by Towfiqu barbhuiya on Unsplash

Why is it important?

This study is significant because it combines two established models of schizophrenia-like symptoms - the NMDAR antagonist model and the Roman High-Avoidance (RHA) rat strain - enhancing the validity of both approaches. It demonstrates strain-specific effects of MK801, with RHA rats showing more pronounced schizophrenia-like behaviors, highlighting the role of genetic factors in the disorder. The research validates the model's predictive power by showing that atypical antipsychotics can reverse or attenuate MK801-induced behavioral alterations, mirroring clinical observations. By addressing both positive and negative symptoms, the study provides a comprehensive view of schizophrenia's complexity. This combined approach offers valuable insights into potential treatment mechanisms, informs future clinical research, and represents a methodological advancement in preclinical schizophrenia modeling. Ultimately, this research contributes to our understanding of schizophrenia and provides a robust platform for evaluating new therapeutic strategies, potentially leading to improved treatments for patients.

Perspectives

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The perspective on schizophrenia treatment is shifting with the emergence of novel approaches like oxytocin alongside atypical antipsychotics. While atypical antipsychotics initially showed promise for better efficacy and tolerability compared to conventional drugs, recent evidence suggests their advantages may be modest, particularly when controlling for dosing differences in trials. Oxytocin, on the other hand, is gaining attention as a potential adjunctive therapy due to its ability to address positive symptoms, negative symptoms, and cognitive deficits while offering a favorable safety profile with fewer metabolic side effects. Genetic factors, such as variations in oxytocin-related genes, may further enable personalized treatment strategies tailored to individual patients. Although oxytocin appears promising, more extensive clinical trials are needed to confirm its efficacy, optimal dosing, and long-term safety. This evolving perspective underscores the need for innovative treatments that can improve outcomes and quality of life for individuals with schizophrenia.

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