Haloperidol rescues the schizophrenia-like phenotype in adulthood after rotenone administration in neonatal rats

Autor(es)

Varga, Thiago Garcia ^[1] ; de Toledo Simoes, Juan Guilherme ^[1] ; Siena, Amanda ^[2] ; Henrique, Elisandra ^[1] ; da Silva, Regina Claudia Barbosa ^[3] ; dos Santos Bioni, Vinicius ^[4] ; Ramos, Aline Camargo ^[5] ; Rosenstock, Tatiana Rosado ^{[2, 6]}

Afiliação do(s) autor(es)

^[1] Santa Casa Sao Paulo Sch Med Sci, Dept Physiol Sci, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Av Prof Lineu Prestes, 1524 Ed Biomed 1, 2 Andar, BR-05508900 Sao Paulo, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Biosci, Santos, SP - Brazil

^[4] Univ Fed Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo - Brazil

^[6] Univ Birmingham, Inst Canc & Genom Sci, Inst Biomed Res, Coll Med & Dent Sci, Birmingham B15 2TT, W Midlands - England

• Tipo de documento: Artigo Científico
• Fonte: Psychopharmacology; v. 238, n. 9, p. 2569-2585, SEP 2021.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 19/17725-4 - O papel da degradação mitocondrial para a homeostase celular: um estudo em células tronco (iPSC) de pacientes com Esclerose Lateral Amiotrófica familiar
• Beneficiário: Thiago Garcia Varga
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 15/02041-1 - O papel das lisinas(K)-deacetilases para a neuroproteção de desordens mitocondriais: perspectivas de terapia epigenética para a esclerose lateral amiotrófica e esquizofrenia
• Beneficiário: Tatiana Rosado Rosenstock
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/26820-0 - Avaliação dos efeitos da hipóxia neonatal no desenvolvimento da esquizofrenia: papel do sistema adenosinérgico
• Beneficiário: Aline Camargo Ramos
• Modalidade de apoio: Bolsas no Brasil - Doutorado