Effect Of Sex Hormones On The Stress Responses In Animal Models Of Depression

Critical interactions between genetic and environmental factors - among which stress is one of the most potent non-genomic factors - are involved in the development of mood disorders.Two main hypotheses have been proposed to underlie depression.One is called "chemical hypothesis" which emphasizes neurochemical imbalance as the cause of depression,including altered function of monoamine system and hyperactivity of the hypothalamic-pituitary-adrenal(HPA) axis.The other one,"network hypothesis" emphasized disturbed neural networks as the cause of this disease,with neurotrophins,growth factors and neural cell adhesion molecules as the molecular mechanism.Sex hormones are involved in depression and stress responses,and this may due to their regulation effect on those neurochemical systems and on those moleculars related to neural network.In the present study,we tested this hypothesis using two animal models(the forced swim test and chronic mild stress model).1.An estrogenic effect of 5α-androstane-3β,17β-diol on the behavioral response to stress and on CRH regulation.The gender difference in behavioral and hormonal response to stress is well known,but the underlying mechanism remains elusive.Arginine-vasopressin(AVP) and corticotrophin-releasing hormone(CRH)are two major regulatory peptides in the brain involved in stress regulation.Their response to stress has been shown to be modulated by sex hormones.The androgen metabolite,5α-androstane-3β,17β-diol (3β-diol),has been identified as an estrogenic hormone.It binds to estrogen receptors (ERs)and modulates estrogen response element mediated promoter activities via the ER pathway.The present Study involved in vitro transfection assays to examine whether 3β-dioi can directly modulate CRH and AVP promoter activity.Our results demonstrate that in CHO-K1 cell lines,when ERs were over-expressed,3β-diol could significantly stimulate CRH and AVP promoter activity through an ER pathway.The effect of 3β-diol on the behavioral,the CRH and the AVP response to stress in the rat was also investigated.We found that chronic,but not acute administration of 3β-diol significantly decreased the immobile duration in the forced swim test.In rats exposed to the forced swim test,CRH mRNA expression in the hypothalamus was enhanced by chronic 3β-diol administration,while the AVP mRNA expression was not affected. These results suggest that 3β-diol may play an anti-depressive role in affective behavior and may have a direct effect on CRH expression.2.Expression of the neural cell adhesion molecule(NCAM)in the prefrontal cortex(PFC)and hippocampus of rats subjected to chronic mild stress: considering testicular influence.The effect of chronic mild stress on emotional behavior and on protein levels of NCAM were evaluated in the PFC and hippocampus of intact or castrated male rat brains.Decreased NCAM expression in the prefrontal cortex was found in the rats subjected to stress,while the protein levels in sub-regions of hippocampus remained unchanged.The study explored whether there was a testicular influence on the behavioral response to stress and on the NCAM expression.We found chronic mild stress induced anhedonia in intact,but not castrated male rats.However,castration did not have influence on the stress induced reduction of NCAM expression.These findings indicate that synthesis and expression of NCAM was involved in chronic mild stress,and the effect of castration on stress related behavior was not mediated by the NCAM pathway.