Discriminative stimulus effects of abused inhalants

滥用吸入剂的歧视性刺激效应

• 批准号: 8793171
• 负责人: KEITH L SHELTON
• 金额: $ 22.09万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793171
• 关键词: Air; Anesthetic Gases; Anesthetics; Animal Model; Animals; Area; Basic Science; Behavioral; Chlorinated Hydrocarbons; Classification; DSM-IV; Data; Dependence; Development; Diagnosis; Discrimination; Funding; Goals; Heterogeneity; Human; In Vitro; Inhalant dose form; Isoflurane; Laboratories; Liquid substance; Literature; Methods; Modeling; Mus; National Institute of Drug Abuse; Neuropharmacology; Nitrous Oxide; Pattern; Pharmaceutical Preparations; Pharmacology; Prevalence; Prevention; Procedures; Public Health; Published Comment; Reporting; Research; Route; Solvents; Specificity; Stimulus; Structure; Substance abuse problem; System; Testing; Toluene; Toxic effect; Training; Trichloroethanes; United States; Work; age group; base; drug discrimination; drug of abuse; follow-up; in vivo; inhalation drug abuse; insight; meetings; member; neurochemistry; receptor; research study; working group

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.

描述（由申请人提供）：吸气滥用在美国和全球范围内提出了严重的，被低估的公共卫生问题。关于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。几个因素可能导致该地区的科学研究缺乏。缺乏适当的方法来探索吸入剂的体内神经化学作用，这显然是一个因素。但是，促进我们对吸入剂的基本理解的另一个更根本的障碍是班级本身的规模和异质性。目前尚不清楚吸入剂在多大程度上应该被视为正式药物类别，因为它是唯一基于给药途径而不是药理作用机理的类别。我们的假设是，小鼠中的吸入药物歧视可用于获取有关吸入剂的体内滥用相关的神经化学作用的基本信息，并允许吸入剂分为基于药理的亚类。在AIM 1中，我们将训练一组小鼠，以区分四种不同的吸入剂中的一种：甲苯，1,1,1-三乙烷（TCE），异氟烷或一氧化二氮。随后，我们将在这四种化合物以及其他代表性的挥发性溶剂和挥发性麻醉药中进行跨测试。我们假设这些跨测试将揭示几个不同的吸入组。如果确认这些发现将支持我们的论点，即可以根据其歧视性刺激来区分吸入剂的亚类。在AIM 2中，我们将确定甲苯，TCE，异氟烷和一氧化二氮作用的药理机理。在甲苯和TCE的情况下，我们将专注于探索我们先前研究中这些化合物的GABAA受体阳性调节作用。具体而言，我们将对选择性调节由特定亚基组成的GABAA受体进行跨测试和拮抗实验。在异氟醚歧视的情况下，我们还将根据我们的初步数据以及可用的体内和体外文献检查其他潜在目标。由于我们缺乏一氧化二氮的初步数据，因此我们选择的跨测试化合物最初将基于文献，然后进一步完善，因为产生了足够的药物歧视结果。在AIM 3中，我们将确认我们理论吸入子类的作用的药理机制。我们将训练动物根据与甲苯，TCE和异氟烷相似的三个其他吸入剂区分，并进行跨测试，并在AIM 2中确定的化合物可以区分这些假设吸入剂亚类中的化合物。这些新训练的吸入剂的类似模式的跨杀伤结果将证实我们吸入分类框架的药理有效性，并提供了有关这些化合物神经药理学的重要见解。