Self-administration of drug combinations: Polydrug abuse

描述（由申请人提供）：多种药物滥用在美国和其他地方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理解有限。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，非人类灵长类动物的药物自我给药，以及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，我们将检验一个最重要的假设，即超级上瘾的强化效应会导致滥用最有问题的药物组合。为了验证这一假设，我们将首先研究选择的拖动组合，以提供有关组合自我管理的基本信息，并建立我们的分析方法。具体目的1是研究具有类似作用机制的药物组合的强化效果。两种兴奋剂（多巴胺转运体配体）将被单独和联合研究，两种阿片类药物（jib受体激动剂）和两种抑制剂（巴比妥酸盐）也将被研究。我们假设，药物类别内的药物在强化作用方面将是加性的。具体目标2是检查跨药理学类别的药物组合，即具有不同的作用机制。将研究兴奋剂-阿片类药物，兴奋剂-抑制剂和阿片类药物-抑制剂的组合。我们假设，在药理学类别（例如，兴奋剂/阿片类药物）中，这些组合在强化作用方面将是非加性的。具体目标3是检查可卡因与其他毒品的常见滥用组合。这一目标的假设是，对人类来说最有问题的组合在强化效果上是超加性的。本提案中的研究旨在制定一个框架，以建立广泛适用的多种药物滥用动物模型。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，我们的模型应该为制定治疗多种药物滥用的改进策略提供关键信息。

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.