BEHAVIORAL PHARMACOLOGY OF ABUSED AEROSOLS--'CRACK'

申请人摘要： 吸食可卡因(可卡因)已成为一种重要的物质 滥用问题，然而，相对较少的尝试来模拟 吸入可卡因碱对动物的生理或行为影响。这个 试图研究可卡因碱基的影响的主要障碍是 缺乏可用于按需生成已定义和 可重复的测试气氛，将实现肺泡沉积模式 在以人类为模型的动物身上。在这方面已经发展了一种方法。 实验室，允许产生精确的、已知的浓度 可卡因基冷凝气雾剂，其颗粒特征为 这样它们很可能会沉积在实验室的肺部 动物。此外，我们已经证明了可卡因的热解产物 碱，甲基ecGonidine(Meg；脱水ecGonine甲酯)碱， 在模型裂解管中，并通过其他方法将可卡因碱输送到 动物或人类，而脑磁图碱基对心血管和 肺功能。在这个项目的未来三年里，我们将使用 研究可卡因碱基、脑磁碱效应的发生器系统 非人灵长类动物(松鼠猴； Saimiri scureus)呼吸含有这些化合物的大气。这些 研究不仅将提供关于可卡因碱影响的经验数据 但也将解决MEG，在数量上可能是 强效吸烟者所遇到的，有助于生理或 吸毒的行为后遗症。 本项目将：i.描述与浓度相关的影响和 暴露在含有以下物质的大气中所致的持续时间相关效应 可卡因碱基、Meg碱基和可卡因/MEG碱气雾剂对心血管的影响 功能(心率、血压)、肺功能(特定呼吸道 电导)和温度(直肠、皮肤)； 调查是否观察到急性耐受现象 (在会议期间)暴露在这些大气中，使用相同的 心血管、肺和体温终点如上所述；考查 心血管、肺和肺血管病变的药理机制 吸入可卡因碱和可卡因/脑磁共振碱的温度效应 松鼠猴子，研究不同的药理物质如何 不同程度地影响心血管和肺反应；火车 松鼠猴子自行管理含有气雾剂的大气 使用先前已证明维持静脉注射的时间表来维持可卡因基础 可卡因自我给药；描述与浓度和持续时间相关的 可卡因碱对自我给药的影响；判断脑磁图碱是否 是自我管理的吗？它是否改变了 松鼠猴子体内的可卡因碱基；V.使用体外技术，研究 脑磁图效应转导的机制(S) 在活体内。 这些研究将对可能的治疗策略产生影响 吸食可卡因对心血管、肺和/或行为的影响 人类。

APPLICANT'S ABSTRACT: Smoking of cocaine base ("crack") has emerged as a significant substance abuse problem yet there have been comparatively few attempts to model the physiological or behavioral effects of inhaled cocaine base in animals. The major obstacle in attempting to study effects of cocaine base has been the lack of technologies available for the generation on demand of a defined and reproducible test atmosphere that will achieve alveolar deposition patterns in animals that model those in humans. A method has been developed in this laboratory which allows the generation of precise, known concentrations of condensation aerosols of cocaine base whose particle characteristics are such that they are likely to be deposited in the lungs of laboratory animals. Additionally, we have shown that a pyrolysis product of cocaine base, methylecgonidine (MEG; anhydroecgonine methyl ester) base, is produced in model crack pipes and by other methods used to deliver cocaine base to animals or humans and that MEG base has effects on cardiovascular and pulmonary function. In the next three years of this project, we shall use the generator system to investigate the effects of cocaine base, MEG base and cocaine/MEG base mixtures in non-human primates (Squirrel monkeys; Saimiri sciureus) breathing atmospheres containing these compounds. These studies will not only provide empirical data on the effects of cocaine base inhalation but will also address whether MEG, in amounts likely to be encountered by the crack smoker, contributes to the physiological or behavioral sequelae of crack use. This project will: i. Describe concentration-related effects and duration-related effects induced by exposure to atmospheres containing cocaine base, MEG base and cocaine/MEG base aerosols on cardiovascular function (heart rate, blood pressure), pulmonary function (specific airway conductance) and temperature (rectal, skin) in squirrel monkeys; ii. Investigate whether acute tolerance phenomena are observed on repeated (within-session) exposure to these atmospheres, using the same cardiovascular, pulmonary and temperature end-points as above; lli. Examine the pharmacological mechanisms underlying the cardiovascular, pulmonary and temperature effects of breathing cocaine base and cocaine/MEG base in squirrel monkeys, investigating how different pharmacological agents may differentially affect cardiovascular and pulmonary responses; iv. Train squirrel monkeys to self-administer atmospheres containing aerosols of cocaine base using schedules that have previously been shown to maintain IV cocaine self-administration; describe concentration- and duration-related effects of cocaine base on self-administration; determine whether MEG base is self-administered and whether it alters the self-administration of cocaine base in squirrel monkeys; v. Using in vitro techniques, investigate the mechanism(s) which may underlie the transduction of the effects of MEG in vivo. These studies will have bearing on possible treatment strategies for cardiovascular, pulmonary and/or behavioral consequences of crack smoking in humans.