Avaliação do hipocampo nas respostas comportamentais e celulares de camundongos submetidos a modelos de ansiedade

Abstract

Anxiety disorders involve several behavioral and autonomic reactions in face of aversive stimuli that may threaten life. These responses are modulated by different neurotransmitters and neural modulators in limbic system structures, such as hippocampus. Among the neurotransmitters involved, it has been attributed to corticotrophin releasing fator (CRF) an important role in regulating anxiety-related defensive behaviors, since the presence of CRFergic neurons and CRF receptors in extrahipolamic sites has been identified. When CRF binds to these Gs-protein coupled receptors it triggers a cascade of intracellular reactions involving the activation of the cAMP/Protein Kinase A (PKA) pathway. This study aimed to evaluate the role of the CRF neurotransmitter and PKA into the hippocampus of mice in anxiety-related behavioral responses when exposed to the Elevated Plus Maze (EPM) through the effects of CP 376395 376395, CRF1 antagonist, and H-89 microinjection, a PKA inhibitor, and rat exposure test (RET), through nuclear expression of Fos protein and effects CP 376395 microinjection. From EPM exposure results, it was possible to verify that the intra-ventral hippocampus (VH) treatment with CP 376395 increased the time in the open arms of the EPM at 3.0nmol dose, however, the 6.0nmol dose increased the number of unprotected head dipping when injected into the dorsal hippocampus (DH) and the number of protected head dipping when injected into VH. None of the doses promoted changes in the stretched-attend posture (SAP) behavior and arrival at the end of the open arms. Microinjection of H-89 at 2.5nmol dose in VH, but not in DH increased the time and number of entries in the open arms, but the 5.0nmol dose increased the number of entries in closed arms. Both doses reduced the expression of protected head dipping behavior on the same subregion. When exposed to RET, there was a decrease only in the number of Fos-positive cells in DH from mice repeatedly exposed to the rat in relation to the toy exposed group. On the other hand, in VH, there was an increase in Fos expression in the groups exposed to the rat in a single or repeated way, in relation to the control and toy exposed groups. The behavioral analysis of these animals revealed that the repeated exposure to the rat decreased the time spent on the surface of the apparatus, as well as the time of contact with the screen and climbing. The single exposure to rat also decreased the time climbing on the screen and increased the number of SAP. Microinjection of CP 376395 at 3.0 and 6.0nmol doses in VH increased the residence time on the surface of the RET, but only the dose of 6.0nmol was able to exert this effect in DH. In relation to the complementary behaviors, only the 3.0nmol dose, injected in VH, decreased the number of SAP. Thus, this study has demonstrated a CRF participation mainly into the VH, in the mediation of anxiety-like behaviors and, moreover, that cAMP/PKA pathway is also involved in the mediation of these effects.