Discriminative stimulus effects of abused inhalants

描述（由申请人提供）：吸入剂滥用在美国和世界范围内是一个严重的、未得到充分重视的公共卫生问题。对吸入剂的基础研究远远落后于对大多数其他类别滥用药物的研究。有几个因素可能是造成该领域科学研究不足的原因。缺乏适当的方法来探索吸入剂与滥用有关的体内神经化学作用显然是一个因素。然而，推进我们对吸入剂的基本理解的另一个更根本的障碍是该类本身的庞大规模和异质性。目前尚不清楚吸入剂在多大程度上应被视为正式的药物类别，因为它是唯一基于给药途径而不是药理作用机制的类别。这是我们的假设，吸入剂药物歧视小鼠可用于获得有关吸入剂在体内滥用相关的神经化学作用的基本信息，以及允许吸入剂被分组为药理学为基础的子类。在目标1中，我们将训练各组小鼠从空气中辨别四种不同吸入剂之一：甲苯，1，1，1-三氯乙烷（TCE），异氟烷或一氧化二氮。我们随后将在这四种化合物之间以及与其他代表性挥发性溶剂和挥发性麻醉剂之间进行交叉试验。我们假设这些交叉测试将揭示几个不同的吸入剂组。如果得到证实，这些研究结果将支持我们的论点，亚类吸入剂可以区分其歧视性的刺激。在目标2中，我们将确定甲苯，三氯乙烯，异氟烷和一氧化二氮的药理作用机制。在甲苯和三氯乙烯的情况下，我们将重点探讨GABAA受体的积极调节作用，这些化合物在我们以前的研究中揭示。具体来说，我们将进行交叉测试和拮抗实验的化合物，选择性地调节GABAA受体组成的特定亚基。在异氟烷辨别的情况下，我们还将根据我们的初步数据以及现有的体内和体外文献检查其他潜在靶点。由于我们缺乏一氧化二氮的初步数据，我们对交叉测试化合物的选择最初将基于文献，然后随着产生足够的药物区分结果而进一步细化。在目标3中，我们将确认我们理论吸入剂亚类的药理学作用机制。我们将训练动物区分基于与甲苯、TCE和异氟烷的相似性选择的另外三种吸入剂，并与目标2中确定的能够区分这些假设吸入剂亚类的化合物进行交叉试验。这些新训练的吸入剂的交叉替代结果的类似模式将证实我们的吸入剂分类框架的药理学有效性，并提供关于这些化合物的神经药理学的重要见解。 公共卫生相关性：由于对这些化合物的滥用相关行为影响的神经药理学基础了解不足，阻碍了吸入剂滥用治疗和预防的进展。本研究将利用小鼠的药物辨别能力来深入了解滥用吸入剂的作用机制，并帮助开发一个合理的基于科学的框架来对这些化合物进行分类。

DESCRIPTION (provided by applicant): Inhalant abuse presents a serious, under-appreciated public health problem in the United States and worldwide. Basic research on inhalants has lagged far behind that on most other classes of abused drugs. Several factors may be responsible for the paucity of scientific studies in the area. Lack of appropriate methods to explore the abuse-related in vivo neurochemical effects of inhalants is clearly one factor. However, another more fundamental impediment to advancing our basic understanding of inhalants is the sheer size and heterogeneity of the class itself. It is currently unclear to what extent inhalants should even be considered a formal drug class since it is the only class based upon route of administration rather than pharmacological mechanisms of action. It is our hypothesis that inhalant drug discrimination in mice can be used to gain basic information concerning the in vivo abuse-related neurochemical effects of inhalants as well as permit inhalants to be grouped into pharmacologically-based subclasses. In Aim 1 we will train groups of mice to discriminate one of four different inhalants from air: toluene, 1,1,1-trichlroethane (TCE), isoflurane or nitrous oxide. We will subsequently conduct cross-tests among these four compounds as well as with other representative volatile solvents and volatile anesthetics. We hypothesize that these cross-tests will reveal several distinct inhalant groups. If confirmed these findings would support our contention that subclasses of inhalants can be differentiated based on their discriminative stimuli. In Aim 2 we will determine the pharmacological mechanisms of action of toluene, TCE, isoflurane and nitrous oxide. In the case of toluene and TCE we will focus on exploring the GABAA receptor positive modulatory effects of these compounds revealed in our prior studies. Specifically we will perform cross-tests and antagonism experiments with compounds that selectively modulate GABAA receptors composed of particular subunits. In the case of the isoflurane discrimination we will also examine other potential targets based on our preliminary data as well as the available in vivo and in vitro literature. As we lack preliminary data with nitrous oxide our choice of cross-test compounds will initially be based on the literature and then further refined as sufficient drug discrimination results are generated. In Aim 3 will we confirm the pharmacological mechanisms of action underlying our theoretical inhalant subclasses. We will train animals to discriminate three additional inhalant selected based on their similarity to toluene, TCE and isoflurane and conduct cross-tests with compounds identified in Aim 2 as being capable of differentiating between these hypothetical inhalants subclasses. A similar pattern of cross-substitution results with these newly trained inhalants will confirm the pharmacological validity of our inhalant classification framework as well as provide important insights on the neuropharmacology of these compounds. PUBLIC HEALTH RELEVANCE: Advancements in the treatment and prevention of inhalant abuse are hampered by a poor understanding of the neuropharmacology underlying the abuse-related behavioral effects of these compounds. The present study will use drug discrimination in mice to provide insights into the mechanisms of action abused inhalants as well as aid in the development of a rational scientifically-based framework for classifying these compounds.