PHARMACOKINETICS OF PSYCHOSTIMULANTS AND REINFORCEMENT

申请人摘要：可卡因和哌醋甲酯（MP）都是 精神兴奋剂然而可卡因被认为是 加强和成瘾药物的滥用，而MP被广泛用于 治疗儿童注意力缺陷障碍。 MP具有类似的亲和力 多巴胺转运蛋白（DAT）的作用。 前期工作从 我们的实验室使用PET和[11 C]可卡因和[11 C]哌甲酯 显示出这两种病毒的分布模式惊人的相似性， 药物在人脑中竞争相同的结合位点。 然而，它们的药代动力学不同。 比可卡因慢得多 我们假设 脑中MP的缓慢清除将干扰 对随后剂量的MP或可卡因的反应，从而降低 可能是“暴饮暴食”的行为。 我们建议测试这些假设 通过研究MP在大鼠体内的药代动力学 脑，其对DAT的抑制和其行为效应， 单次和重复给药。我们还将研究 MP给药对脑内可卡因结合的影响。 我们建议 使用PET结合：[11 C]哌甲酯测量大脑 MP，d-苏型-[11 C]哌甲酯的药代动力学，以测量DAT MP单次和重复iv给药后的占用率， [11 C]可卡因，以评价药理学剂量的 MP. 对于最后一个实验，我们选择使用口服给药 而不是IV，因为“缓释”的潜在有用性 MP在可卡因成瘾治疗中的应用 与此同时，我们还将 评估口服MP对行为反应的影响， 药理剂量iv MP。 我们的工作假设如下： (1)MP的初始摄取以及DAT的快速抑制 由MP，将与“高”，但持续抑制 DAT的不会。 当在DAT期间给予第二剂时 仍然受到抑制，“高”将显着下降，尽管 相当于甚至更大百分比的DAT抑制。 (2)口服MP给药将抑制[11 C]可卡因和 [11 C]MP在相当程度上，将减少 iv MP诱导的“高”。 了解MP之间的关系 脑中的药代动力学，其DAT的占用长度及其 精神活性影响不仅对于理解 MP和其他精神兴奋剂药物的成瘾潜力， 开发治疗可卡因成瘾的治疗策略。

APPLICANT'S ABSTRACT: Cocaine and methylphenidate (MP) are both psychostimulant drugs. Yet cocaine is considered one of the most reinforcing and addictive drugs of abuse, while MP is widely used to treat attention deficit disorder in children. MP has a similar affinity for the dopamine transporter (DAT) as cocaine. Preliminary work from our laboratory using PET and [11C]cocaine and [11C]methylphenidate showed a striking similarity for the pattern of distribution of these two drugs in the human brain with competition for the same binding sites. However, they differ in their pharmacokinetics.MP's clearance from brain is significantly slower than that of cocaine. We hypothesize that the slow clearance of MP in brain will interfere with the magnitude of the response to a subsequent dose of MP, or cocaine, thus decreasing the likelihood of "bingeing" behavior. We propose to test these hypotheses by investigating the relation between the pharmacokinetics of MP in brain, its inhibition of the DATs and its behavioral effects after single and repeated administration.We will also investigate the effects of MP administration on the binding of cocaine in brain. We propose to use PET in conjunction with: [11C]methylphenidate to measure brain pharmacokinetics of MP, d-threo-[11C]methylphenidate to measure DAT occupancy after single and repeated iv MP administration and [11C]cocaine to evaluate binding inhibition by pharmacological doses of MP. For this last experiment we have chosen to use oral administration rather than iv because of the potential usefulness of a "slow release" form of MP in the treatment of cocaine addict. In parallel we will also evaluate the effects of oral MP on the behavioral response to a pharmacological dose of iv MP. Our working hypotheses are as follows: (1) The initial uptake of MP, as well as the fast inhibition of the DAT by MP, will be associated with the "high", but the continuous inhibition of the DAT will not. When a second dose is administered while the DATs are still inhibited, the "high" will be significantly decreased despite equivalent or even a larger percent of DAT inhibition. (2) Oral MP administration, will inhibit binding of [11C]cocaine and [11C]MP to a comparable extent and will decrease the magnitude of the iv MP-induced "high". Understanding the relation between MP's pharmacokinetics in brain, its length of occupation of the DAT and its psychoactive effects is important not only in understanding the addictive potential of MP and other psychostimulant drugs but also for the development of therapeutic strategies to treat cocaine addiction.