Self-administration of drug combinations: Polydrug abuse

在美国和其他地方，多药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是有限的。实验室研究可以帮助更准确地确定 这些机制有助于以合理的方式制定干预措施。 这项提案中概述的研究将使用实验室模型，即非人类的药物自我给药。 灵长类，以及目前了解药物相互作用的药理学方法，以研究自身 阻力组合的管理。更具体地说，我们将测试最重要的假设，即超 令人上瘾的强化效应助长了最有问题的拖拽组合的滥用。 为了验证这一假设，我们将首先研究选定的阻力组合，以提供有关 自我管理的组合和建立我们的分析方法。具体目标1是研究 具有类似作用机制的拖拉剂组合的强化效果。两种兴奋剂 (多巴胺转运体配体)将被单独和联合研究，两个阿片类药物(ji受体)也将被研究 激动剂)和两种抑制剂(巴比妥类)。我们假设，在一个药理学类别中拖累 在增强效果方面是相加的。具体目标2是检查拖拽的组合 药理类，即具有不同的作用机制。兴奋剂-阿片类药物，兴奋剂-镇静剂和 将研究阿片类药物和镇静剂的组合。我们假设跨药理学类别(例如， 兴奋剂/阿片类药物)这些组合在增强效果方面将是非相加的。具体目标3是 检查经常被滥用的可卡因与其他毒品的组合。这个目标的假设是 对人类来说最有问题的组合在增强效果上是超级相加的。 这项建议中的研究旨在制定一个框架，以建立 广泛适用的多效性滥用的动物模型。在这方面，我们的模式应该有助于理解 阻力组合强化效应的神经行为学基础。此外，我们的模型应该 为制定改进的多药滥用治疗战略提供关键信息。

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 (ji 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 polydrag 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 polydrag abuse.