Discriminative stimulus effects of abused inhalants

描述(申请人提供)：吸入剂滥用在美国是一个主要的社会和医学问题，在一些发展中国家被描述为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，人们对吸入剂产生行为影响的细胞活动知之甚少。在探索滥用药物行为影响的细胞机制方面，一种非常有价值的方法是药物辨别程序。药物在动物身上的歧视性刺激效应被认为是对人类主观效应的模拟。由于技术原因，对滥用吸入剂的歧视性刺激效应的检查仅限于在经过训练以辨别其他注射药物的动物身上测试这些吸入剂。虽然这些方法被证明是有用的，表明滥用吸入剂可能对包括GABAA和NMDA受体在内的多个神经递质受体系统具有复杂的作用，但需要更直接的方法。最近，我们开发了一种新的程序，在这种程序中，小鼠可以很容易地被训练来辨别吸入挥发性化合物本身的主观影响。我们对典型的滥用吸入剂甲苯的初步研究表明，它的内感CMS效应足以产生对吸入的甲苯线索的完全替代。在克服了主要的技术挑战后，这项提案的第一个具体目标是对吸入甲苯的歧视性刺激效应的起效速度和持续时间进行更多的参数描述。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区别刺激效果。这将允许根据其与甲苯的相似程度对滥用吸入剂进行分类，否则，由于其种类繁多，很难对其进行分类。最终的具体目标是确定甲苯和第二种滥用吸入剂1，1，1-三氯乙烷的内感刺激效应背后的细胞作用部位。这些研究将大大增强我们对滥用吸入剂如何在受体水平上发挥作用以产生其行为行为的理解，并可能为开发吸入剂滥用的选择性治疗提供重要的见解。

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.