Immunopharmacotherapy for Methamphetamine Addiction

描述（由申请人提供）：滥用和成瘾，d-甲基苯丙胺（METH）干扰个人健康，职业表现，人际关系和财务状况的许多方面。甲基苯丙胺滥用和甲基苯丙胺贸易的行为后果也使整个美国的法律的和紧急医疗资源紧张。因此，甲基苯丙胺是一个重大和持续的公共卫生问题。目前用于METH成瘾的治疗方法不完全有效，并且不存在用于METH成瘾的批准的药物疗法。最近在使用免疫方法治疗可卡因和尼古丁成瘾的早期临床试验中取得的成功激发了人们对创造类似方法治疗甲基苯丙胺成瘾的兴趣。在该项目的初始供资期间开展的工作已经创造了MH 6疫苗，该疫苗已被证明可产生抗体，将甲硫氨酸隔离在血液中。该疫苗还减弱了METH对自发活动、体温调节和METH静脉内自我给药的影响。新的研究试图通过确定不同载体蛋白和佐剂的作用来优化疫苗以获得更高的抗体滴度。在大鼠中的研究将使用药物相关奖励的聚合模型，包括颅内自我刺激奖励和中脑核壳中的多巴胺反应，以确定疫苗如何改变自我给药的获得。额外的工作将确定优化的疫苗是否可以使用长期访问程序防止升级到不受管制的METH摄入量，以及疫苗是否可以逆转既定的自我管理模式。这些研究将在优化抗METH疫苗的设计和可能的翻译应用方面取得重大进展。

DESCRIPTION (provided by applicant): The abuse of, and addiction to, d-methamphetamine (METH) interferes with many aspects of personal health, vocational performance, interpersonal relationships and financial well-being. Behavioral consequences of METH abuse and the METH trade also strain legal and emergency medical resources throughout the US. METH is therefore a significant and continuing public health concern. Current therapeutic approaches for METH addiction are less than completely effective and no approved pharmacotherapies for METH addiction exist. Recent successes in early clinical trials using immunotherapeutic approaches for cocaine and nicotine addiction have motivated interest in creating similar approaches for methamphetamine addiction. Work under the initial funding interval of this project has created the MH6 vaccine which was shown to generate antibodies which sequester METH in the blood. The vaccine also attenuated METH effects on locomotor activity, thermoregulation and intravenous self-administration of METH. New studies seek to optimize the vaccine for higher antibody titer by determining effects of different carrier proteins and adjuvants. Studies in rats will use converging models of drug-related reward, including intracranial self-stimulation reward and the dopamine response in the nucleus accumbens shell, to determine how the vaccine alters the acquisition of self- administration. Additional work will determine if an optimized vaccine can prevent the escalation to unregulated METH intake using a long-access procedure and if the vaccine can reverse an established self-administration pattern. Together these studies will make significant progress on optimizing both the design and likely translational application of an anti-METH vaccine.