Joint Action Analysis of Poly-drug Withdrawal

多种药物戒断的联合作用分析

• 批准号: 6913407
• 负责人: ROBERT B RAFFA
• 金额: $ 15.05万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913407
• 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

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）：尽管许多药物滥用者使用多种药物，但在多种药物暴露后戒断时，没有严格的药物间相互作用（数学上称为“联合作用分析”）量化。这种分析的严格性随着测量尽可能接近作用部位的药物浓度的能力而增加。啮齿动物和猴模型具有与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）。事实上，使用这些模型的研究得出了相互矛盾的结果。PI最近在一个模型中开发了一个方便和敏感的指标，该模型不太受上述限制的影响。该度量标准经过精心选择，与生理相关，利用了Planaria的优势，Planaria在建模哺乳动物行为和精神药理学效应方面具有悠久而丰富的生产使用历史。Planaria与这些研究特别相关，因为它们的类小脑CNS（能够学习和记忆的原始大脑和脊髓）和哺乳动物神经递质系统（例如，多巴胺能、5-HT和阿片样物质）。相对于其他模型的显著优势包括：敏感的戒断措施;测量药物浓度的能力;获得精确ED 50值的能力，以及药物之间相对不存在PK干扰。拮抗剂敏感的、受体介导的药物滥用（可卡因和阿片类药物）戒断反应已经在Planaria中可重复地引发，并由PI以适合联合作用分析的形式进行量化。该提案的目的是：（1）将该指标应用于代表性滥用药物和暴露时间表，然后（2）将这些数据纳入PI和合作研究者先前开发和发布的联合行动分析（例如，Zmix与Zadd值的比较）。如果停用两种药物产生相似或不同的行为，或者即使一种药物没有产生可测量的影响（合作研究者已经建立了分析此类“单组”相互作用的方法），则此类分析适用。这些研究的结果将集中于并建立未来的基础，更机械的，研究使用，例如，电生理学或分子生物学技术。更好地了解多种药物滥用对戒断的影响，可能有助于开发更好的临床治疗。