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Joint Action Analysis of Poly-drug Withdrawal

多种药物戒断的联合作用分析

基本信息

批准号：
7060756
负责人：
ROBERT B RAFFA
金额：
$ 14.7万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7060756
关键词：
Platyhelminthes amphetamines behavior test cocaine dopamine drug interactions drug withdrawal mathematical model morphine opiate alkaloid pharmacokinetics serotonin statistics /biometry substance abuse related disorder toxicant interaction

项目摘要

DESCRIPTION (provided by applicant): Despite the fact that many drug abusers engage in poly-drug use, there has been no rigorous quantification of the drug-drug interactions (known mathematically as 'joint action analysis') in withdrawal after poly-drug exposure. The rigor of such analysis increases with the ability to measure drug concentration as close to the site of action as possible. Rodent and monkey models have inherent limitations related to inability to know drug concentration - rather than dose - due to pharmacokinetic factors (i.e., the two drugs can affect each other's absorption, distribution, metabolism, or excretion). Indeed, studies using these models have yielded conflicting results. The PI has recently developed a convenient and sensitive metric in a model that is less susceptible to the above limitations. The metric, carefully selected to be physiologically-relevant, capitalizes on the advantages of Planaria, which have a long and rich history of productive use for modeling mammalian behaviors and psychopharmacologic effects. Planaria are particularly relevant for these studies because of their mammalian-like CNS (a primitive brain and spinal cord that is capable of learning and memory) and mammalian neurotransmitter systems (e.g., dopaminergic, 5-HT, and opioid). Significant advantages over other models include: a sensitive measure of withdrawal; an ability to measure drug concentration; ability to obtain precise ED50 values, and relative absence of PK interference between drugs. Antagonist-sensitive, receptor-mediated withdrawal from drugs of abuse (cocaine and opioid) have already been reproducibly elicited in Planaria and quantified by the PI in a form that is amenable to joint-action analysis. The aims of the proposal are: (1) to apply the metric to representative abused drugs and exposure schedules, then (2) subject these data to joint-action analyses previously developed and published by the PI and Co-Investigator (e.g., comparison of Zmix vs Zadd values). Such analyses are applicable if the withdrawal from two drugs produces either similar or different behaviors, or even if one drug does not produce measurable effects (the Co-Investigator has established the methodology to analyze such 'one-arm' interaction). The results of these studies will focus and establish the basis for future, more mechanistic, studies using, e.g., electrophysiologic or molecular biology techniques. An improved understanding of how withdrawal is influenced by poly-drug abuse could lead to development of enhanced clinical treatment.

描述(由申请人提供)：尽管许多吸毒者使用多种药物，但在接触多种药物后戒断时药物与药物的相互作用(数学上称为‘联合作用分析’)还没有得到严格的量化。随着测量药物浓度的能力尽可能靠近作用部位，这种分析的严谨性增加了。由于药代动力学因素(即，这两种药物可以影响彼此的吸收、分布、代谢或排泄)，啮齿动物和猴子的模型存在固有的局限性，无法知道药物浓度而不是剂量。事实上，使用这些模型的研究产生了相互矛盾的结果。PI最近在一个不太容易受到上述限制影响的模型中开发了一种方便而敏感的指标。该指标经过精心挑选，与生理相关，利用了Planaria的优势，Planaria在模拟哺乳动物行为和精神药理效应方面有着悠久而丰富的生产性使用历史。与这些研究特别相关的是其类似哺乳动物的中枢神经系统(一种能够学习和记忆的原始大脑和脊髓)和哺乳动物的神经递质系统(例如，多巴胺能、5-羟色胺和阿片类物质)。与其他模型相比，显著的优势包括：对戒断的敏感测量；测量药物浓度的能力；获得准确的ED50值的能力，以及药物之间相对不存在PK干扰。拮抗剂敏感的、受体介导的滥用药物(可卡因和阿片类药物)戒断已经在Planaria被重复地诱导，并由PI以一种适合联合作用分析的形式进行量化。该提案的目的是：(1)将该指标应用于典型的滥用药物和暴露时间表，然后(2)对这些数据进行由PI和联合调查员先前开发和发布的联合行动分析(例如，ZMix和Zadd值的比较)。如果停用两种药物会产生相似或不同的行为，或者甚至一种药物不会产生可测量的效果(合作调查者已经建立了分析这种“单臂”相互作用的方法)，这种分析就适用。这些研究的结果将集中并为未来使用例如电生理学或分子生物学技术进行更机械化的研究奠定基础。更好地了解多种药物滥用是如何影响戒断的，可能会导致加强临床治疗的发展。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Withdrawal-like behavior in planarians is dependent on drug exposure duration.

涡虫的戒断行为取决于药物暴露时间。

DOI：
10.1016/j.neulet.2008.04.086
发表时间：
2008
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Sacavage,Steve;Patel,Hiren;Zielinski,Mike;Acker,Jeneane;Phillips,AustinG;Raffa,RobertB;Rawls,ScottM
通讯作者：
Rawls,ScottM

Description and quantification of cocaine withdrawal signs in Planaria.

涡虫中可卡因戒断症状的描述和量化。