Desenvolvimento de um modelo de transtorno bipolar a partir de fatores ambientais

Abstract

Mental disorders, particularly bipolar disorder, is a health problem in the world since the beginning of this century. Animal models for bipolar disorder separately have induced endophenotypes of mania and depression. Two environmental models were combined to provide a model with a mixed phenotype of mania and depression: paradoxical sleep deprivation (PSD), for manic phenotype, and inescapable exposure to hot air blast (HAB), for depressive phenotype. The experimental design consisted of two phases: phase I (stress induction) and phase II (evaluation of behavioral effect). The Control group (N = 10) was maintained only under the standard housing conditions during the two phases. In PSP group (N = 10), animals in Phase I were exposed to five sessions paradoxical sleep deprivation (PSP) interspersed daily for ten days. In JAQ group (N = 10), animals in Phase I were exposed to five hot air jet sessions (JAQ) interspersed daily for ten days. In PSP + JAQ group (N = 10), the animals were exposed in Phase I for 10 days to PSP and JAQ sessions intercalated with each other daily. In Phase II, the inductive contingencies were interrupted in order to verify their behavioral effects. Two behavioral tests were performed: i) open field to evaluate locomotor, emotional and impulsivity parameters; and ii) sensitivity to appetitive stimulus, in order to evaluate the reward motivational function. To probe the pathophysiology, biochemical and molecular tests for oxidative damage were performed in hippocampus and pre-frontal cortex samples, as well as quantification of dopamine transporter by immunoblotting. According to the results, the chronic exposure of the animals to environmental stressors, isolated or combined (HAB and / or PSD), induced post-stress behavioral changes similar to some mood disorder endophenotypes with the combined stressors (PSD+HAB) specifically inducing an endophenotype similar to bipolar disorder. Regarding biological tests, there was evidence of oxidative damage in the hippocampus and increased expression of dopamine transporter in the prefrontal cortex of animals submitted to PSD+HAB. From this, a probable neurochemical mechanism that would explain the deregulation of the dopaminergic system could involve the loss of the cortico-limbic connection and the cortical control over the reward system, leading to the alteration of the behavioral sensitivity to rewards and corroborating a motivational/emotional hypothesis of bipolar disorder.