Discriminative stimulus effects of abused inhalants

滥用吸入剂的歧视性刺激效应

• 批准号: 7262020
• 负责人: KEITH L SHELTON
• 金额: $ 18.04万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262020
• 关键词: Acetylcholine; Anesthetics; Animals; Attenuated; Behavioral; Breathing; Complex; Cues; Developed Countries; Developing Countries; Development; Discrimination; Dopamine; Drug abuse; Exposure to; Human; Inhalant dose form; Inhalation Exposure; Medical; Methods; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurotransmitter Receptor; Neurotransmitters; Nicotinic Receptors; Opioid; Opioid Receptor; Pharmaceutical Preparations; Procedures; Serotonin; Site; Speed; Stimulus; System; Testing; Thinking; Time; Toluene; Training; Trichloroethanes; United States; base; drug discrimination; drug of abuse; inhalation drug abuse; insight; novel; receptor; serotonin receptor; social; vapor

DESCRIPTION (provided by applicant): Inhalant abuse is a major social and medical problem in the United States and has been characterized as the predominant drug abuse problem in some developing countries. Despite this, less is know about the cellular actions of inhalants which produce their behavioral effects than for virtually any other major drug of abuse. One method that has been extremely valuable for exploring the cellular mechanisms underlying the behavioral effects of abused drugs is the drug discrimination procedure. The discriminative stimulus effects of drugs in animals are thought to model subjective effects in humans. For technical reasons, the examination of the discriminative stimulus effects of abused inhalants has been limited to testing these inhalants in animals trained to discriminate other injected drugs. While these methods have proven useful in suggesting that abused inhalants may have complex actions at multiple neurotransmitter receptor systems including, GABAA and NMDA receptors, a more direct approach is needed. Recently we have developed a novel procedure in which mice can readily be trained to discriminate the subjective effects of inhaled volatile compounds themselves. Our preliminary studies with a prototypic abused inhalant, toluene, suggest that its interoceptive CMS effects are sufficient to produce full substitution to the inhaled toluene cue. With the major technical challenges overcome, the first specific aim of this proposal is do a more parametric characterization of the speed of onset and duration of the discriminative stimulus effects of inhaled toluene. The second specific aim is to compare and contrast the discriminative stimulus effects of inhaled toluene to other abused inhalants, volatile anesthetics and gasses. This will allow abused inhalants, which are otherwise difficult to categorize given their wide diversity, to be categorized according to their degree of similarity to toluene. The final specific aim is to determine the cellular sites of action that underlie the interoceptive stimulus effects of toluene and a second abused inhalant 1,1,1-trichloroethane. These studies should greatly enhance our understanding of how abused inhalants act at the receptor level to produce their behavioral actions and may provide important insights useful for the development of selective treatments for inhalant abuse.

描述（由申请人提供）：吸入滥用是美国的一个主要社会和医学问题，在某些发展中国家中被认为是主要的药物滥用问题。尽管如此，与几乎任何其他主要的滥用药物相比，对吸入剂产生其行为影响的细胞作用的了解少。一种对于探索滥用药物行为影响的细胞机制非常有价值的方法是药物歧视程序。人们认为药物在动物中的歧视性刺激作用被认为是对人类的主观影响。出于技术原因，滥用吸入剂的歧视性刺激作用的检查仅限于测试这些吸入剂的吸入剂，该吸入剂在接受训练以区分其他注射药物的动物中。尽管这些方法已被证明在暗示滥用吸入剂可能在多个神经递质受体系统（包括GABAA和NMDA受体）上具有复杂的作用有用，但需要更直接的方法。最近，我们开发了一种新的程序，可以轻松地训练小鼠，以区分吸入挥发性化合物本身的主观作用。我们对原型滥用吸入剂的初步研究表明，其互感的CMS效应足以在吸入的甲苯提示中完全取代。由于克服了主要的技术挑战，该提案的第一个具体目的是对吸入甲苯的判别刺激效应的发作速度和持续时间进行更参数表征。第二个具体目的是比较和对比吸入的甲苯与其他滥用吸入剂，挥发性麻醉和气体的歧视性刺激作用。这将允许滥用的吸入剂，鉴于其广泛的多样性，否则很难将其分类，可以根据与甲苯的相似程度进行分类。最终的具体目的是确定甲苯和第二次滥用吸入的1,1,1-三氯乙烷的互感刺激作用的作用细胞部位。这些研究应极大地增强我们对滥用吸入物在受体水平上的作用以产生其行为行为的理解，并可能提供重要的见解，可用于开发选择性治疗吸入滥用。