Self-administration of drug combinations: Polydrug abuse

描述(由申请人提供)：在美国和其他地方，多药滥用是一个严重的公共卫生问题，尽管我们对控制多药滥用的机制的了解有限。实验室研究可以帮助更准确地建立这些机制，从而有助于制定合理的干预措施。这项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目前了解药物相互作用的药理学方法来研究阻力组合的自我给药。更具体地说，我们将测试最重要的假设，即超级令人上瘾的强化效应导致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，以提供有关组合自我管理的基本信息，并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药物组合的增强效果。将单独和联合研究两种兴奋剂(多巴胺转运体配体)，以及两种阿片类药物(JIB受体激动剂)和两种镇静剂(巴比妥酸盐)。我们假设药理类药物中的药物在增强作用方面是相加的。具体目标2是检查不同药理类别的药物组合，即具有不同作用机制的药物。将研究兴奋剂-阿片类药物、兴奋剂-镇静剂和阿片类药物-镇静剂组合。我们假设，在整个药理学类别(例如，兴奋剂/阿片类药物)中，这些组合在增强效果方面将是非相加的。具体目标3是审查通常被滥用的可卡因与其他毒品的组合。这一目标的假设是，在人类身上最有问题的组合在增强效果方面是超级相加的。这项建议中的研究旨在开发一个框架，以建立一个广泛适用的多种药物滥用的动物模型。在这方面，我们的模型应该有助于理解阻力组合强化效应的神经行为基础。此外，我们的模型应该为制定改进的治疗多种药物滥用的战略提供关键信息。

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.