BEHAVIORAL PHARMACOLOGY OF ABUSED AEROSOLS--'CRACK'

申请人摘要： 吸食可卡因碱（“快克”）已成为一种重要的物质， 然而，相对而言，很少有人试图建立一个 吸入可卡因碱对动物的生理或行为影响。 的 试图研究可卡因碱作用的主要障碍是 缺乏可用于按需生产确定的 可重现的试验气氛，将实现肺泡沉积模式 在动物身上模仿人类身上的那些。 一种方法已经开发出来， 该实验室允许产生精确的，已知浓度的 可卡因碱的凝结气溶胶，其颗粒特征是 使得它们很可能沉积在实验室的肺部 动物 此外，我们还发现可卡因的热解产物 产生一种碱，甲基芽子碱（MEG;脱水芽子碱甲酯）碱 在对裂化管道建模中以及通过用于将可卡因碱输送到 动物或人类，MEG碱对心血管和 肺功能 在这个项目的未来三年，我们将使用 发生器系统研究可卡因碱、MEG碱 和可卡因/MEG碱混合物在非人灵长类动物（松鼠猴; 松鼠猴（Saimiri sciureus）呼吸含有这些化合物的空气。 这些 这些研究不仅将提供关于可卡因碱影响的经验数据， 吸入，但也将解决是否MEG，在数量可能是 所遇到的裂缝吸烟者，有助于生理或 可卡因使用的行为后遗症 该项目将：i。描述浓度相关效应， 暴露于含有以下物质的大气中引起的持续时间相关效应 可卡因碱、MEG碱和可卡因/MEG碱气雾剂对心血管系统的影响 功能（心率、血压）、肺功能（特定气道 电导）和温度（直肠，皮肤）; ii. 研究是否观察到急性耐受现象， （会议期间）暴露于这些气氛，使用相同的 如上所述的心血管、肺和温度终点; LII. 审查 心血管、肺和 呼吸可卡因碱和可卡因/MEG碱的温度效应 松鼠猴，研究不同的药物如何 差异地影响心血管和肺响应; iv. 火车 松鼠猴自我管理含有气溶胶的空气， 可卡因碱使用的时间表，以前已被证明维持IV 可卡因自我给药;描述浓度和持续时间相关 可卡因碱对自我给药的影响;确定MEG碱是否 是自我管理的，它是否改变了自我管理的 可卡因碱在松鼠猴;五.使用体外技术，调查 可能导致MEG效应转导的机制 in vivo. 这些研究将对可能的治疗策略产生影响， 心血管，肺和/或行为后果的裂纹吸烟， 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.