Modelos animais de mania bipolar: comportamento, neuroinflamação e sistema adenosinérgico

• Ano de defesa: 2018
• Autor(a) principal: Goncalves, Maria Carolina Bittencourt [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Neuropsychiatry; Bipolar disease; Chemical induced bipolar disease; Immunological system; Purine; Immunology; Neuropsiquiatria; Transtorno bipolar; Sistema imunológico; Purina; Imunologia; Transtorno bipolar induzido quimicamente
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=6744181; https://repositorio.unifesp.br/handle/11600/52165

Bipolar disorder (BD) stands out as one of the least deciphered psychiatric pathologies to date due to the great difficulty in understanding and investigating its pathophysiology and etiology. BD alternate between different neurochemical and neurobiological states manifested under different endophenotypes and mood swings polarized between mania and depression. Considering that BD has no cure and the treatments currently available are nonspecific, it is necessary to invest in a deep understanding of its biological bases. Currently, the disease is known to manifest in a multifaceted way, involving dysfunctions in neurotransmission systems, energy metabolism, neurodegeneration and inflammatory processes, among others. Since the purinergic system is an important pathway of neural and peripheral modulation, acting on the balance of different physiological conditions altered in bipolar patients, the present study aimed 1. to investigate an association between this system and neuroinflammatory processes in different brain regions through the induction of a maniclike behavior in rodents; and 2. to identify an efficient model of maniclike behavior chemically induced in rodents. Initially, a previous characterization and optimization of available models of chemicallyinduced mania was performed in the presence and absence of the main mood stabilizers: lithium and valproate. Once defined and chosen the best animal model to induce maniclike behavior, we proceed with further investigation of neuroinflammatory conditions and a possible purinergic dysfunction. The results showed that using GBR12909 to chemicallyinduce mania is more efficacious and ethically more viable than the inducing with ouabain. Also, males responded partially better to GBR12909 induction than females. In order to better mimic a recurrent and / or lasting manic episode, a GBR12909induced model was also proposed in a chronic manner, based on multiple applications of the drug at a concentration of 12.5 mg/kg. This model resulted in a better behavioral response, longlasting and partially able to be prevented by lithium pretreatment. Thus, in the animals chronically induced to mania, we investigated the neuroinflammatory profile in different brain regions and its consequent influence on the systemic immune response and on the purinergic signaling system based on in silico analyses. The results indicate that the striatal and cerebellar regions show a greater systemic inflammatory response and adenosinergic dysfunction, whereas a higher resistance to the inflammatory process is observed in the prefrontal cortex. The hippocampal region, however, presents a transition profile between the anti and proinflammatory processes, possibly being associated to mechanisms other than the monoaminergic modulation by GBR12909.