PHARMACOKINETICS OF PSYCHOSTIMULANTS AND REINFORCEMENT

申请人摘要：可卡因和哌醋甲酯(MP)都是 精神刺激剂。然而，可卡因被认为是最 强化和成瘾药物的滥用，而MP则被广泛用于 治疗儿童注意力缺陷障碍。MP也有类似的亲和力 作为可卡因的多巴胺转运体(DAT)。前期工作来自 我们的实验室使用PET、[11C]可卡因和[11C]哌醋甲酯 两者的分布模式有惊人的相似之处 人类大脑中的药物与竞争相同的结合部位。 然而，它们的药代动力学不同。MP的脑清除量 比可卡因慢得多。我们假设 MP在大脑中的缓慢清除会干扰 对随后剂量的MP或可卡因的反应，从而降低 “暴饮暴食”行为的可能性。我们建议对这些假设进行检验 通过研究甲基强的松龙在人体内的药代动力学 脑及其对DAT的抑制作用及其对行为的影响 单次和多次给药。我们还将调查这些影响 MP给药对脑内可卡因结合的影响。我们建议 PET与[11C]哌醋甲酯联合应用测量脑功能 MP，d-苏氨酸-[11C]哌酸甲酯测定DAT的药代动力学 单次和多次静脉注射MP后的入住率和 [11C]评估可卡因的药理剂量对结合抑制的影响 议员在最后一个实验中，我们选择了口服给药。 而不是静脉注射，因为“缓慢释放”的潜在用处。 甲氧西林在治疗可卡因成瘾中的作用同时，我们还将 评价口服甲基强的松龙对动物行为反应的影响 药理剂量静脉注射甲基强的松龙。我们的工作假设如下： (1)MP的初始摄取和DAT的快速抑制 受MP的影响，会联想到“高”，但不断受到抑制 DAT的人不会。当DAT在第二次给药时 仍然是被抑制的，那么尽管 相当于甚至更大百分比的DAT抑制。 (2)口服MP可抑制[11C]可卡因和 [11C]MP达到可比的程度，并将降低 静脉注射甲基强的松龙可引起“兴奋”。理解国会议员与国会议员的关系 药物在脑内的药代动力学及其在DAT中的占位时间 精神活性效应不仅在理解 MP和其他精神刺激性药物的成瘾潜力 治疗可卡因成瘾的治疗策略的发展。

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.