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，兴趣消失，以及感觉无助，这通常会导致生活质量下降，以及在许多情况下自杀。尽管抗抑郁药在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-HT和NE的再摄取或分解而发生的，但这些单胺的突触水平的增加不能单独解释抗抑郁药的治疗作用。最近的研究表明，慢性抗抑郁治疗（ADT）改变基因表达，特别是cAMP信号转导级联的成分。ADT治疗效果的延迟与细胞内途径中基因表达的变化一致，并且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具有相反的作用，部分原因是对神经营养因子表达的相反作用。我们推测，压力和抗抑郁药管理基因表达谱的相互变化。这项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，并将这些谱与应激时观察到的变化进行比较。然而，有必要区分ADT的急性和慢性变化，因为只有慢性ADT才具有治疗作用。这可以通过在ADT后的不同时间点通过微阵列分析比较表达谱来实现。基因表达的变化将在大鼠大脑的海马和齿状回中表征。这将增加我们对抗抑郁治疗作用机制的理解，并可能导致新的治疗靶点。 这些研究的结果应导致旨在扩展这些发现的ROI提案。简而言之，进一步的研究将涉及调节通过病毒介导的基因在离散脑区域中的表达而鉴定的基因的表达和转基因小鼠的产生，用于在应激和抑郁的行为模型中的研究。

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.