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）：在美国和世界范围内，吸入剂滥用是一个严重的、未被重视的公共卫生问题。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科学研究的缺乏。缺乏适当的方法来探索吸入剂滥用相关的体内神经化学效应显然是一个因素。然而，促进我们对吸入剂的基本了解的另一个更根本的障碍是该类本身的绝对规模和异质性。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。我们的假设是，小鼠的吸入药物鉴别可以用来获得有关吸入剂体内滥用相关神经化学作用的基本信息，并允许将吸入剂分为基于药理学的亚类。在目标1中，我们将训练一组老鼠从空气中辨别四种不同的吸入物：甲苯、1,1,1-三氯乙烷（TCE）、异氟烷或一氧化二氮。随后，我们将对这四种化合物以及其他具有代表性的挥发性溶剂和挥发性麻醉剂进行交叉测试。我们假设这些交叉测试将揭示几个不同的吸入剂组。如果得到证实，这些发现将支持我们的论点，即吸入剂的亚类可以根据其区别性刺激来区分。在目标2中，我们将确定甲苯、TCE、异氟醚和一氧化二氮的药理作用机制。在甲苯和TCE的情况下，我们将重点探索这些化合物在我们之前的研究中揭示的GABAA受体的正调节作用。具体来说，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。在异氟醚鉴别的情况下，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目标。由于我们缺乏关于氧化亚氮的初步数据，交叉测试化合物的选择将首先基于文献，然后在产生足够的药物鉴别结果时进一步完善。在Aim 3中，我们将确认我们的理论吸入剂亚类的药理学作用机制。我们将训练动物区分根据其与甲苯、TCE和异氟烷的相似性选择的另外三种吸入剂，并与Aim 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测试。与这些新训练的吸入剂类似的交叉取代结果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见解。