Gene Expression Profile of Antidepressants

描述（由申请人提供）：抑郁症的行为特征是情绪低落，无法体验快乐，兴趣减退，感觉没有价值，这些通常会导致生活质量下降，在许多情况下还会导致自杀。尽管在抗抑郁药物的神经生物学和神经药理学方面取得了重大进展，但抗抑郁药物治疗作用的分子机制尚未确定。虽然大多数抗抑郁药的急性作用是通过抑制5-羟色胺和NE的再摄取或分解而发生的，但仅增加这些单胺的突触水平并不能解释抗抑郁药的治疗作用。近年来的研究表明，慢性抗抑郁治疗（ADT）可以改变基因表达，尤其是cAMP信号转导级联的组成部分。ADT治疗效果的延迟与细胞内通路中基因表达的变化相一致，人们认为这些变化介导了抗抑郁药的治疗效果。众所周知，压力和抗抑郁药对神经元生长和脆弱性有相反的作用，部分原因是对神经营养因子的表达有相反的作用。我们假设压力和抗抑郁药物管理在基因表达谱上有相互的变化。R21探索性资助的目的是表征不同类别ADT的基因表达谱，包括5-HT和去甲肾上腺素选择性再摄取抑制剂和ECS，并将这些谱与应激下观察到的变化进行比较。然而，有必要区分ADT反应的急性和慢性改变，因为只有慢性ADT已被证明具有治疗效果。这可以通过在ADT和ADT后的不同时间点通过微阵列分析比较表达谱来完成。大鼠脑海马和齿状回的基因表达变化将被表征。这将增加我们对抗抑郁药物治疗作用机制的理解，并可能导致新的治疗靶点。

DESCRIPTION (provided by applicant): Depression is characterize behaviorally by depressed mood, inability to experience pleasure, withdrawal of interest, and feelings of worthlessness which can often result in a debilitating quality of life, as well as suicide in many cases. Despite the significant advances that have been made in neurobiology and neuropharmacology of antidepressants, the molecular mechanisms underlying the actions antidepressant treatment have not been identified. Although the acute action of most antidepressants occurs via inhibition of the reuptake or breakdown 5-HT and NE, increased synaptic levels of these monoamines alone cannot account for the therapeutic action of antidepressants. Recent studies have shown that chronic antidepressant treatment (ADT) alters gene expression, especially components of cAMP signal transduction cascade. The delay in the therapeutic effects of ADT coincides with changes in gene expression in intracellular pathways, and it is thought that these changes mediate the therapeutic effects of antidepressants. It is known that stress and antidepressants have opposing actions on neuronal growth and vulnerability, in part due to the opposing effects on expression of neurotrophic factors. We hypothesize that stress and antidepressant administration have reciprocal changes in gene expression profiles. The aim of this R21 Exploratory Grant is to characterize the gene expression profiles to different classes of ADT, including 5-HT and norepinephrine selective reuptake inhibitors and ECS, and compare these profiles with changes observed with stress. It is however necessary to distinguish between acute and chronic alterations in response to ADT as only chronic ADT has been shown to possess therapeutic effects. This can be accomplished by comparing expression profiles by microarray analysis at various time points after and ADT. Gene expression changes will be characterized in the hippocampus and dentate gyrus of rat brain. This will increase our understanding of the mechanisms underlying the actions of antidepressant treatment and could lead to novel therapeutic targets. The results from these studies should lead to an ROl proposal aimed at extending these findings. Briefly, further studies would involve modulating the expression of genes identified by viral-mediated expression of genes in discrete brain regions and generation of transgenic mice, for study in behavioral models of stress and depression.