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、被低估的公共卫生问题。对吸入剂的基础研究远远落后于大多数其他类别的滥用药物。有几个因素可能是该地区缺乏科学研究的原因。缺乏适当的方法来探索吸入剂与滥用相关的体内神经化学影响显然是一个因素。然而，促进我们对吸入剂的基本理解的另一个更根本的障碍是吸入剂本身的巨大规模和异质性。目前还不清楚吸入剂在多大程度上应该被视为正式的药物类别，因为它是基于给药途径而不是药理作用机制的唯一类别。我们的假设是，在小鼠身上的吸入性药物识别可以用来获得关于吸入剂在体内滥用相关的神经化学影响的基本信息，并允许将吸入剂分类为基于药理学的亚类。在目标1中，我们将训练一组小鼠从空气中辨别四种不同的吸入剂之一：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具有代表性的挥发性溶剂和挥发性麻醉剂之间进行交叉测试。我们假设，这些交叉测试将揭示几个不同的吸入剂类别。如果得到证实，这些发现将支持我们的论点，即可以根据吸入剂的歧视性刺激来区分亚类吸入剂。在目标2中，我们将确定甲苯、三氯乙烯、异氟醚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，我们将重点探索我们先前研究中揭示的这些化合物的GABAA受体正调控作用。具体地说，我们将对选择性调节由特定亚基组成的GABAA受体的化合物进行交叉测试和拮抗实验。在异氟烷歧视的情况下，我们还将基于我们的初步数据以及现有的体内和体外文献来检查其他潜在的靶点。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识别结果而进一步完善。在目标3中，我们将确认我们的理论吸入剂亚类背后的药理作用机制。我们将训练动物根据它们与甲苯、三氯乙烯和异氟醚的相似性选择另外三种吸入剂，并与目标2中确定的能够区分这些假想吸入剂亚类的化合物进行交叉测试。与这些新训练的吸入剂的交叉替代结果相似的模式将证实我们的吸入剂分类框架的药理学有效性，并为这些化合物的神经药理学提供重要的见解。 公共卫生相关性：由于对这些化合物与滥用有关的行为影响背后的神经药理学缺乏了解，在治疗和预防吸入剂滥用方面的进展受到阻碍。本研究将利用小鼠身上的药物歧视来深入了解滥用吸入剂的作用机制，并帮助制定合理的、以科学为基础的框架，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.