Abstract
Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive deficits of schizophrenia (SZ), respectively, that were reverted by Hal, but not MPD. Rot-treated rodents also display a prodromal-related phenotype at P35. Overall, our results seem to present a new SZ animal model as a consequence of mitochondrial inhibition during a critical neurodevelopmental period. Therefore, our study is crucial not only to elucidate the relevance of mitochondrial function in the etiology of SZ but also to fulfill the need for new and trustworthy experimentation models and, likewise, provide possibilities to new therapeutic avenues for this burdensome disorder.
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Acknowledgements
We thank the animal facilities’ personnel for animal care, as well as the employees from the Department of Physiological Science of the Santa Casa de São Paulo School of Medical Science. Moreover, we are also grateful to Claudenice Moreira dos Santos, the technician at the Department of Pharmacology at the Federal University of São Paulo that performed the HPLC experiment. We would like to give a particular recognition to Prof. Dr. Fabio Cardoso Cruz (Department of Pharmacology at the Federal University of São Paulo) for letting us use the passive avoidance apparatus and assisting in the HPLC experiment. Moreover, we would like to give a special credit to Prof. Mariana Bendlin Calzavara (Department of Psychiatry at the Federal University of São Paulo) for the consulting, and Prof. Regina Silva (Department of Pharmacology at the Federal University of São Paulo) for the DA measurement.
Funding
This work was supported by São Paulo Research Foundation (FAPESP) (ref. 2015/02041–1) and Fundação de Amparo à Pesquisa of Santa Casa de São Paulo School of Medical Science (FCMSCSP) (2015–2016). PIBIC and FAPESP (2019/17725–4) supported TGV, and PIBIC supported JGTS; both are undergraduate medical students. AS was supported by PROSUC/CAPES during her Master’s, and EH and VSB were supported by Master CAPES fellowship. ACR was supported by FAPESP (2015/26820–0).
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TGV and JGTS performed together all behavioral experiments. Both of them, together with AS and EH, analyzed the data and assembled the graphics. ACR helped us with the Hal/MDP protocol and treatments, in addition to measuring the dopamine turnover; VSB also performed the HPLC experiment. TGV, JGTS, and AS wrote the manuscript. TRR designed the study, wrote the protocols, and wrote the final version. RCBS and ACR revised the manuscript and contributed to the discussion section. All authors approved the final version of the manuscript.
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The authors declare no conflict of interest.
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Thiago Garcia Varga and Juan Guilherme de Toledo Simões are equally contributed to this study
Highlights
• Neonatal Rotenone induces Schizophrenia-like phenotype during adulthood
• Hal, but not MPD, rescued Rot-induced increased locomotor activity
• Both Hal and MPD reverted Rot-induced decreased social interaction
• Hal-induced rescue of diminished aversive memory after Rot administration
• Rot-induced behavioral changes at P35 animals
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Varga, T.G., de Toledo Simões, J.G., Siena, A. et al. Haloperidol rescues the schizophrenia-like phenotype in adulthood after rotenone administration in neonatal rats. Psychopharmacology 238, 2569–2585 (2021). https://doi.org/10.1007/s00213-021-05880-1
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DOI: https://doi.org/10.1007/s00213-021-05880-1