Self-administration of drug combinations: Polydrug abuse

描述（由申请人提供）：在美国和其他地方，多种药物滥用是一个严重的公共卫生问题，尽管我们对控制多种药物滥用的机制的了解有限。实验室研究可以帮助更精确地建立这些机制，从而有助于制定干预措施的合理方法。本提案中概述的研究将使用实验室模型、非人灵长类动物的药物自我给药和当前了解药物相互作用的药理学方法来研究药物组合的自我给药。更具体地说，我们将测试总体假设，即超级成瘾性强化效应有助于滥用最有问题的药物组合。为了检验这一假设，我们将首先研究药物组合选择提供基本信息的自我管理的组合，并建立我们的分析方法。具体目标1是研究具有可比作用机制的药物组合的增强作用。两种兴奋剂（多巴胺转运蛋白配体）将单独和联合研究，两种阿片类药物（jib受体激动剂）和两种抑制剂（巴比妥类）也将进行研究。我们假设，药物类内的药物将在加强作用方面是累加的。具体目标2是检查药理学类别中的药物组合，即，不同的作用机制。将研究兴奋剂-阿片类药物、兴奋剂-阿片类药物和阿片类药物-阿片类药物组合。我们假设，在药理学类别中（例如，兴奋剂/阿片样物质），这些组合在增强效果方面将是非加和的。具体目标3是检查可卡因与其他药物的常见滥用组合。这一目标的假设是，在人类中最有问题的组合在其强化效果上是超级累加的。本提案中的研究旨在为建立广泛适用的多种药物滥用动物模型制定一个框架。在这方面，我们的模型应该有助于理解阻力组合的强化效应的神经行为基础。此外，我们的模型应提供关键信息的发展，改善策略，治疗多种药物滥用。

DESCRIPTION (provided by applicant): Polydrug abuse is a serious public health problem in the US and elsewhere, though our understanding of the mechanisms controlling polydrug abuse is limited. Laboratory research can help establish more precisely these mechanisms and, thereby, contribute to rational approaches to the development of interventions. The research outlined in this proposal will use a laboratory model, drug self-administration by non-human primates, and current pharmacological approaches to understanding drug interactions, to study the self- administration of drag combinations. More particularly, we will test the overarching hypothesis that super- addictive reinforcing effects contribute to the abuse of the most problematic drag-combinations. To test this hypothesis, we will first study drag combinations selected to provide basic information about self-administration of combinations and to establish our analytical approach. Specific Aim 1 is to study the reinforcing effects of combinations of drags with comparable mechanisms of action. Two stimulants (dopamine transporter ligands) will be studied alone and in combination, as will two opioids (jib receptor agonists) and two depressants (barbiturates). We hypothesize that drags within a pharmacological class will be additive in terms of reinforcing effects. Specific Aim 2 is to examine combinations of drags across pharmacological class, i.e., with different mechanisms of action. Stimulant-opioid, stimulant-depressant and opioid-depressant combinations will be studied. We hypothesize that across pharmacological class (e.g., stimulant/opioid) these combinations will be non-additive in terms of reinforcing effects. Specific Aim 3 is to examine commonly abused combinations of cocaine with other drags. The hypothesis of this aim is that the combinations that are most problematic in humans are super-additive in their reinforcing effects. The studies in this proposal are designed with the aim of developing a framework for establishing a broadly applicable animal model of polydrug abuse. In this respect, our model should facilitate understanding neurobehavioral underpinnings of the reinforcing effects of drag combinations. Moreover, our model should provide key information for the development of improved strategies for the treatment of polydrug abuse.