Discriminative stimulus effects of abused inhalants

描述（由申请人提供）：吸入剂滥用是美国的一个主要社会和医学问题，在一些发展中国家已被定性为主要的药物滥用问题。尽管如此，对吸入剂产生行为效应的细胞作用的了解比几乎任何其他主要滥用药物都要少。药物辨别程序是一种非常有价值的方法，可以用来探索滥用药物行为效应的细胞机制。药物在动物身上的区别性刺激效应被认为是人类主观效应的模型。由于技术原因，对滥用吸入剂的区别性刺激作用的检查仅限于在经过训练能够区别其他注射药物的动物身上测试这些吸入剂。虽然这些方法已被证明可用于表明滥用的吸入剂可能对多种神经递质受体系统（包括GABAA和NMDA受体）具有复杂的作用，但需要更直接的方法。最近，我们已经开发了一种新的程序，在该程序中，小鼠可以很容易地被训练来辨别吸入的挥发性化合物本身的主观影响。我们的初步研究与原型滥用吸入剂，甲苯，表明其内感受CMS的影响是足以产生完全取代吸入甲苯线索。随着主要技术挑战的克服，该提案的第一个具体目标是对吸入甲苯的区别性刺激效应的发作速度和持续时间进行更多的参数表征。第二个具体目标是比较和对比吸入甲苯与其他滥用吸入剂、挥发性麻醉剂和气体的辨别刺激作用。这将使被滥用的吸入剂能够根据其与甲苯的相似程度进行分类，否则由于其广泛的多样性而难以对其进行分类。最后的具体目标是确定的细胞网站的行动，甲苯和第二滥用吸入剂1，1，1-三氯乙烷的内感受性刺激的影响。这些研究应大大提高我们的理解如何滥用吸入剂在受体水平上产生的行为行动，并可能提供重要的见解，为吸入剂滥用的选择性治疗的发展有用。

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.