ANTIDEPRESSANTS AND SIGNAL TRANSDUCTION IN BRAIN
抗抑郁药和大脑信号转导
基本信息
- 批准号:2415933
- 负责人:
- 金额:$ 16.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1989
- 资助国家:美国
- 起止时间:1989-09-01 至 2000-04-30
- 项目状态:已结题
- 来源:
- 关键词:MAO inhibitors antidepressants antisense nucleic acid beta adrenergic receptor biological signal transduction cAMP response element binding protein cyclic AMP cyclic AMP receptors drug administration rate /duration electroconvulsive therapy enzyme activity frontal lobe /cortex gene expression growth factor receptors in situ hybridization laboratory rat neuropharmacology neurotrophic factors northern blottings protein kinase A psychotropic drugs receptor expression serotonin inhibitor serotonin receptor stress western blottings
项目摘要
Major depressive illness is alleviated by chronic, but not acute,
administration of antidepressant drugs and electroconvulsive seizures
(ECS). While the mechanism of action of these widely used treatments is
not clearly understood, the delay in therapeutic efficacy has led to the
hypothesis that some adaptive alteration in neuronal function must occur
over the course of treatment. Preclinical and clinical studies support
the hypothesis that the norepinephrine (NE) and serotonin (5-HT)
neurotransmitter systems are involved in the therapeutic action of
antidepressant treatments, but regulation of neurotransmitter levels
and/or receptors cannot fully account for such actions. This is not
surprising, since different types of antidepressants exert different
effects on NE and 5-HT neurotransmitter systems. An updated hypothesis
is that the actions of antidepressant treatments are mediated by
adaptations of postreceptor, intracellular sites and regulation of gene
expression. Our preliminary studies demonstrate that chronic, but not
acute, administration of antidepressants increases levels of cAMP-
dependent protein kinase (PKA) enzyme activity in particulate fractions,
and levels of cAMP response element binding protein (CREB)
immunoreactivity in rat frontal cortex. We have also found that
antidepressant treatments increase levels of brain derived neurotrophic
factor (BDNF) mRNA and its receptor, trkB, in frontal cortex and
hippocampus, and that induction of BDNF is blocked by local infusion of
CREB antisense, but not sense, oligonucleotides, providing a functional
link between the PKA-CREB cascade and expression of BDNF. Based on these
results, we hypothesize that antidepressant treatments activate the PKA-
CREB cascade and increase expression of BDNF. To test this hypothesis,
we will determine the influence of different types of antidepressant
treatments, including electroconvulsive seizure, monoamine oxidase
inhibitors, selective NE and 5-HT re-uptake inhibitors, and several
atypical antidepressants on levels of PKA and CREB and expression of BDNF
and trkB mRNA in rat limbic brain regions. The relevance and significance
of these postreceptor adaptations will be verified by several criteria,
including analysis of pharmacological specificity, determined by
examination of nonantidepressant psychotropic drug treatments
(haloperidol, cocaine, diazepam, and morphine), selective dose responses,
time course, and regional specificity. PKA will be analyzed by standard
enzyme assays and Western blot analysis, CREB immunoreactivity, both
phosphorylated and dephosphorylated forms, will be determined by Western
blot, CREB function will be determined by CRE gel shift analysis, and
BDNF and trkB mRNA will be determined by RNase protection, northern blot,
and in situ hybridization. Activation of the PKA-CREB cascade and
induction of BDNF could mediate long-term adaptations of neuronal
function in response to antidepressant treatments.
慢性疾病受到慢性疾病的缓解
给药抗抑郁药和电抽搐癫痫发作
(EC)。尽管这些广泛使用治疗的作用机理是
尚不清楚,治疗功效的延迟导致了
假设必须发生一些神经元功能的自适应改变
在治疗过程中。临床前和临床研究支持
去甲肾上腺素(NE)和5-羟色胺(5-HT)的假设
神经递质系统参与了
抗抑郁药,但调节神经递质水平
和/或受体无法完全考虑此类行动。这不是
令人惊讶的是,由于不同类型的抗抑郁药会施加不同的
对NE和5-HT神经递质系统的影响。更新的假设
是抗抑郁治疗的作用是由
后受体,细胞内部位和基因调节的适应
表达。我们的初步研究表明,慢性
急性,抗抑郁药的给药增加了营地的水平 -
颗粒分数中的依赖性蛋白激酶(PKA)酶活性
和cAMP响应元件结合蛋白(CREB)的水平
大鼠额叶皮层的免疫反应性。我们还发现
抗抑郁治疗增加了脑衍生的神经营养的水平
因子(BDNF)mRNA及其受体TRKB,在额叶皮质中
海马,并且BDNF的诱导被局部输注所阻断
CREB反义,但没有意义,寡核苷酸,提供功能性
PKA-CREB级联和BDNF表达之间的联系。基于这些
结果,我们假设抗抑郁药激活PKA-
Creb级联并增加BDNF的表达。为了检验这一假设,
我们将确定不同类型的抗抑郁药的影响
治疗,包括电击癫痫发作,单胺氧化酶
抑制剂,选择性NE和5-HT再摄取抑制剂,几个
PKA和CREB水平的非典型抗抑郁药以及BDNF的表达
大鼠边缘大脑区域中的TRKB mRNA。相关性和意义
这些后受体适应将通过几个标准验证
包括分析药理学特异性,由
检查非抗抑郁药的精神药物治疗
(氟哌啶醇,可卡因,地西ep和吗啡),选择性剂量反应,
时间课程和区域特异性。 PKA将通过标准分析
酶测定和蛋白质印迹分析,CREB免疫反应性,都
磷酸化和去磷酸化的形式将由西方确定
印迹,CREB功能将通过CRE凝胶移位分析确定,并且
BDNF和TRKB mRNA将由RNase Protection,Northern Blot,
和原位杂交。激活PKA-CREB级联和
BDNF的诱导可以介导神经元的长期适应
响应抗抑郁药的功能。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
RONALD S. DUMAN其他文献
RONALD S. DUMAN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('RONALD S. DUMAN', 18)}}的其他基金
Synaptic mechanisms underlying the rapid antidepressant actions of scopolamine
东莨菪碱快速抗抑郁作用的突触机制
- 批准号:
8934161 - 财政年份:2014
- 资助金额:
$ 16.99万 - 项目类别:
Synaptic mechanisms underlying the rapid antidepressant actions of scopolamine
东莨菪碱快速抗抑郁作用的突触机制
- 批准号:
8810419 - 财政年份:2014
- 资助金额:
$ 16.99万 - 项目类别:
Role of mTOR and Synaptogenesis in the Actions of Rapid-Acting Antidepressants
mTOR 和突触发生在速效抗抑郁药作用中的作用
- 批准号:
8738247 - 财政年份:2013
- 资助金额:
$ 16.99万 - 项目类别:
Role of mTOR and Synaptogenesis in the Actions of Rapid-Acting Antidepressants
mTOR 和突触发生在速效抗抑郁药作用中的作用
- 批准号:
8812007 - 财政年份:2011
- 资助金额:
$ 16.99万 - 项目类别:
Role of mTOR and synaptic protein synthesis in the rapid antidepressant actions o
mTOR 和突触蛋白合成在快速抗抑郁作用中的作用
- 批准号:
8097791 - 财政年份:2011
- 资助金额:
$ 16.99万 - 项目类别:
Role of mTOR and synaptic protein synthesis in the rapid antidepressant actions o
mTOR 和突触蛋白合成在快速抗抑郁作用中的作用
- 批准号:
8230821 - 财政年份:2011
- 资助金额:
$ 16.99万 - 项目类别:
Role of mTOR and Synaptogenesis in the Actions of Rapid-Acting Antidepressants
mTOR 和突触发生在速效抗抑郁药作用中的作用
- 批准号:
8434258 - 财政年份:2011
- 资助金额:
$ 16.99万 - 项目类别:
Role of mTOR and Synaptogenesis in the Actions of Rapid-Acting Antidepressants
mTOR 和突触发生在速效抗抑郁药作用中的作用
- 批准号:
8635386 - 财政年份:2011
- 资助金额:
$ 16.99万 - 项目类别:
The ability of the transcription factor CREB in the Nac to regulate mood
Nac中转录因子CREB调节情绪的能力
- 批准号:
8114141 - 财政年份:2010
- 资助金额:
$ 16.99万 - 项目类别:
The ability of the transcription factor CREB in the Nac to regulate mood
Nac中转录因子CREB调节情绪的能力
- 批准号:
7664379 - 财政年份:2008
- 资助金额:
$ 16.99万 - 项目类别:
相似国自然基金
抗抑郁药氟西汀对泥蚶受精的影响及其作用机理研究
- 批准号:
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:面上项目
2种临床常用抗抑郁药对肠道菌群的影响研究
- 批准号:
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:面上项目
2种临床常用抗抑郁药对肠道菌群的影响研究
- 批准号:32170064
- 批准年份:2021
- 资助金额:58.00 万元
- 项目类别:面上项目
多脑区跨膜蛋白质组学技术用于抗抑郁潜在药靶发现
- 批准号:32171439
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:面上项目
抗抑郁药氟西汀对泥蚶受精的影响及其作用机理研究
- 批准号:32172944
- 批准年份:2021
- 资助金额:58.00 万元
- 项目类别:面上项目
相似海外基金
Estrogen and CaM Kinase IV in the Limbic System
边缘系统中的雌激素和 CaM 激酶 IV
- 批准号:
6731275 - 财政年份:2003
- 资助金额:
$ 16.99万 - 项目类别:
Estrogen and CaM Kinase IV in the Limbic System
边缘系统中的雌激素和 CaM 激酶 IV
- 批准号:
6807552 - 财政年份:2003
- 资助金额:
$ 16.99万 - 项目类别:
Estrogen and CaM Kinase IV in the Limbic System
边缘系统中的雌激素和 CaM 激酶 IV
- 批准号:
7117346 - 财政年份:2003
- 资助金额:
$ 16.99万 - 项目类别:
Estrogen and CaM Kinase IV in the Limbic System
边缘系统中的雌激素和 CaM 激酶 IV
- 批准号:
6945832 - 财政年份:2003
- 资助金额:
$ 16.99万 - 项目类别: