MOLECULAR MECHANISMS OF DIAZEPAM TOLERANCE
地西泮耐受性的分子机制
基本信息
- 批准号:2035157
- 负责人:
- 金额:$ 9.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-01-01 至 1999-12-31
- 项目状态:已结题
- 来源:
- 关键词:GABA receptor anticonvulsants antipsychotic agents behavior test benzodiazepines brain mapping cognition diazepam drug administration rate /duration drug tolerance immunocytochemistry laboratory rat messenger RNA neurons neuropharmacology polymerase chain reaction protein structure receptor expression tissue /cell culture
项目摘要
DESCRIPTION (Adapted from applicant's abstract): Tolerance to
benzodiazepines (BZ) limits their clinical use of anticonvulsants,
anxiolytic and antipanic agents. In the clinical practice to maintain the
level of drug efficacy the BZ doses are increased to overcome tolerance and
this often leads to physical dependence. We must understand the mechanisms
of BZ tolerance in order to overcome the problems in their clinical use and
we believe that this will also bring about an initial understanding of how
GABAergic transmission is regulated. BZ can be classified as FULL or
PARTIAL allosteric modulators of GABA action at GABA-a receptors (FAM and
PAM, respectively). Both drug classes act on GABA-a receptors that include
one alpha1-5 and one gamma2-3 subunit in their structure, but their
intrinsic activity in amplifying GABA action differs. Diazepam, (a FAM),
but not imidazenil, (a PAM) induces tolerance in rodents. In preliminary
studies, we have shown that in tolerance rats there is a change in the
expression of mRNAs encoding for alpha1, gamma2 and alpha5 GABA-a receptor
subunits which reverses when tolerance is reversed. Such changes are not
present in rats receiving imidazenil in doses equipotent to those of
diazepam that induce tolerance. These two drugs will be used as research
tools to explore the mechanism of diazepam tolerance. We hypothesize that
tolerance to diazepam is triggered by an alteration of GABA-a receptor
subunit expression restricted to functionally dedicated brain areas. We
propose a systematic investigation of the mechanism of diazepam tolerance in
rats with the following aims: (1) Determine onset and duration of diazepam
tolerance to its anticonvulsant, anticonflict and cognition disrupting
action using as a contrast imidazemil, (2) PCR analysis changes in 14
subunit mRNA content in 28 brain areas at the onset and termination of
diazepam tolerance and test whether imidazenil produces similar changes or
antagonizes diazepam changes, (3) Measure with gold immunolabeling in brain
slices the content of 8 different GABA-a receptor subunits in pertinent
brain areas of diazepam tolerant rats using imidazenil as a contrast and/or
as antagonist and (4) Study changes of subunit expression in neuronal
membranes of dissociated cultures prepared from pertinent brain areas of
tolerant rats; determine receptor coexpression of pertinent subunits with
double-immunolabelling with gold particles of different size.
描述(改编自申请人的摘要):对
苯二氮类药物(BZ)限制了其抗惊厥药物的临床应用,
抗焦虑和抗恐慌剂。在临床实践中保持
药物疗效水平BZ剂量增加以克服耐受性和
这往往会导致身体上的依赖。我们必须了解其中的机制
以克服其在临床应用中存在的问题和
我们相信,这也将带来对如何
GABA能传递是受调控的。BZ可分为Full或
GABA作用于GABA-a受体的部分变构调节剂(FAM和
分别为PAM)。这两类药物都作用于GABA-a受体,包括
它们的结构中有一个α1-5和一个γ2-3亚基,但它们的
增强GABA作用的内在活性不同。安定(FAM),
但不是咪达西尼,(一种PAM)可以诱导啮齿动物的耐受性。在预赛中
研究表明,在耐受大鼠中,
编码α1、γ2和α5 GABA-a受体的mRNAs表达
公差反转时反转的子单位。这样的变化并不是
在接受咪达西尼治疗的大鼠中存在,剂量与
能引起耐受性的安定。这两种药物将被用作研究
探讨安定耐受机制的工具。我们假设
对安定的耐受性是由GABA-a受体的变化引起的
亚基的表达仅限于特定的大脑功能区。我们
建议对大鼠安定耐受机制进行系统研究
目的如下:(1)确定安定的起效时间和持续时间
对其抗惊厥、抗冲突和认知障碍的耐受性
用咪达西米作为对照,(2)PCR分析14例变化
28个脑区发病和终止时亚单位mRNA含量的变化
安定耐受性和检测咪达西尼是否产生类似的变化或
拮抗安定变化;(3)脑内金标记法测定
切片8种不同的GABA-a受体亚基的含量
咪达西尼作为对照和/或地西安定耐受大鼠的脑区
AS拮抗剂和(4)研究神经元亚单位表达的变化
从相关脑区制备的分离培养物膜
耐受大鼠;测定相关亚基的受体共表达
用不同大小的金粒子进行双重免疫标记。
项目成果
期刊论文数量(0)
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专利数量(0)
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ERMINIO COSTA的其他文献
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{{ truncateString('ERMINIO COSTA', 18)}}的其他基金
GABAergic molecular pathology in schizophrenia
精神分裂症的 GABA 分子病理学
- 批准号:
7365158 - 财政年份:2005
- 资助金额:
$ 9.41万 - 项目类别:
GABAergic molecular pathology in schizophrenia
精神分裂症的 GABA 分子病理学
- 批准号:
6918287 - 财政年份:2005
- 资助金额:
$ 9.41万 - 项目类别:
GABAergic molecular pathology in schizophrenia
精神分裂症的 GABA 分子病理学
- 批准号:
7192398 - 财政年份:2005
- 资助金额:
$ 9.41万 - 项目类别:
GABAergic molecular pathology in schizophrenia
精神分裂症的 GABA 分子病理学
- 批准号:
7034548 - 财政年份:2005
- 资助金额:
$ 9.41万 - 项目类别:
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