The involvement of the dysfunction of transcrption factor in the pathogenesis of stress-related psychiatric disorders

为探讨应激相关精神障碍（SRPDs）的发病机制，本研究观察了应激和/或抗抑郁药物对大鼠额叶皮质和海马cAMP反应元件结合蛋白（CREB）磷酸化和钙调神经磷酸酶（CaN）活性的影响。而急性抗抑郁药治疗显着诱导p-CREB的水平，慢性以及慢性加急性抗抑郁药治疗p-CREB的表达没有变化。抗抑郁药慢性预处理可下调ARS对p-CREB的诱导作用，但ARS和抗抑郁药治疗对CaN mRNA水平均无显著影响。与此相反，虽然ARS显着诱导的丝氨酸/苏氨酸磷酸酶活性的CaN，无论是急性和慢性给药的抗抑郁药显着上调CaN activity.To研究CREB磷酸化的失衡是否参与了应激的脆弱性，影响的p-CREB的表达和CaN活性的单一延长的压力（SPS），其次是ARS。SPS后ARS组p-CREB表达和CaN活性均高于ARS组，但差异无显著性，提示CREB磷酸化介导的基因表达变化可能在SRPDs的发病机制中起重要作用。p-CREB和CaN活性在应激反应中的显著诱导可能参与了应激易感性的获得。

To elucidate the pathogenesis of stress-related psychiatric disorders (SRPDs), I examined whether stress and/or antidepressant drug treatments could regulate the phosphorylation of cAMP response element binding protein (CREB) and calcineurin (CaN) activity in rat frontal cortex and hippocampus.A marked induction of phospho CREB (p-CREB) followed by the transient significant downregulation was found in response to acute restraint stress (ARS). Whereas acute antidepressant treatments significantly induced the levels of p-CREB, chronic as well as chronic plus acute antidepressant treatments had no change in p-CREB expression. Chronic pretreatment with antidepressant downregulated the induction of p-CREB in response to ARS.Neither ARS nor antidepressant treatments had a significant change in the levels of CaN mRNA. In contrast, while ARS significantly induced the serine/threonine phosphatase activity of CaN, both acute and chronic administration of antidepressants significantly upregulated CaN activity.To examine whether the imbalance of CREB phosphorylation was involved in the stress vulnerability, the influence of single prolonged stress (SPS) followed by ARS on p-CREB expression and CaN activity. Both p-CREB expression and CaN activity by SPS followed by ARS were higher than those by ARS, but the differences did not reach the significance.Based on these findings, it is suggested that the changes in gene expression mediated by CREB phosphorylation could play an important role in the pathogenesis of SRPDs, and the marked induction of p-CREB and CaN activity in response to stress may be involved in the acquisition of stress vulnerability.