Trace amine receptor-mediated methamphetamine response in brain

大脑中微量胺受体介导的甲基苯丙胺反应

• 批准号: 9206890
• 负责人: Aaron J. Janowsky
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206890
• 关键词: Affect; Agonist; Alleles; American; Amination; Amines; Animal Behavior; Behavior; Behavioral; Brain; Cell physiology; Chemicals; Chronic; Clinical; Cocaine; Cultured Cells; Data; Diagnosis; Etiology; Exhibits; Gene Transfer; Genes; Genetic Polymorphism; Health; Human; Intake; Knock-out; Knockout Mice; Laboratories; Mammalian Cell; Mediating; Medical center; Mental disorders; Methamphetamine; Methamphetamine dependence; Mouse Strains; Mus; Oregon; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Physiological; Physiology; Psychological reinforcement; Recombinants; Reporting; Resources; Role; Signal Transduction; Single Nucleotide Polymorphism; Symptoms; Synapses; Taste aversion; United States; Variant; Veterans; Viral; analog; cost; design; drinking; experimental study; genetic variant; in vivo; methamphetamine abuse; methamphetamine effect; methamphetamine exposure; methamphetamine use; natural hypothermia; novel; novel therapeutics; patient population; public health relevance; receptor; response; symptom treatment; therapeutic target; tool; translational approach

 DESCRIPTION (provided by applicant): Project Summary A recent study by the Rand Corporation indicated that methamphetamine (MA) abuse costs the United States over $20-$60 billion/year. About 10 million Americans have used MA at least once. Chronic MA use has far reaching health consequences and a tremendous societal impact. At V.A. Medical Centers MA abuse is associated with increased use of facility resources and deleterious consequences for veterans, such as additional psychiatric disorders. There are currently no approved medications for treatment of MA addiction, and consequently there is an urgent need to discover MA pharmacotherapies. Recently the trace amine-associated receptor 1 (TAAR1) has been identified as a target for MA and its analogues, but not for cocaine. Therefore, TAAR1 is possibly a unique MA target. TAAR1 knockout (KO) mice show increased activity in response to MA and we have shown that they preferentially consume more MA as compared to their wild-type (wt) littermates. Additionally, KO mice, and mice expressing a non-functional TAAR1 are insensitive to the aversive effects of MA (hypothermia, conditioned taste aversion). There are no commercially available selective agonists or antagonists for the TAAR1. Developing new drugs that interfere with MA-mediated effects at TAAR1 has clinical implications in that (partial) agonists could serve as treatments to possibly limit MA intake. Conversely, TAAR1 antagonists can serve as important pharmacological tools to further study of TAAR1-mediated physiology. This project will use a translational approach to characterize cultured cells that express multiple non- synonymous single nucleotide polymorphisms (SNP) of human TAAR1. In addition, we will use viral-mediated gene transfer of human TAAR1 polymorphisms in mice to determine the effects of synthesized novel agents designed to both affect human TAAR1 function and to compete pharmacologically with MA. Results from these experiments will identify the role of TAAR1 in MA-mediated pharmacology and behaviors and will characterize potential new pharmacotherapies, synthesized in our laboratories, which can be used to treat specific symptoms of MA abuse and addiction.

 描述（由申请人提供）： 项目摘要兰德公司最近的一项研究表明，甲基苯丙胺（MA）的滥用损失了美国超过200亿美元/年。大约1000万美国人至少使用了一次。慢性MA使用具有很大的健康后果和巨大的社会影响。在V.A.医疗中心MA滥用与增加设施资源的使用和对退伍军人的有害后果有关，例如其他精神病患者。目前尚无批准治疗MA成瘾的药物，因此迫切需要发现MA药物治疗。最近，痕量胺相关的受体1（TAAR1）已被确定为MA及其类似物的靶标，但不是可卡因的目标。因此，TAAR1可能是独特的MA目标。 TAAR1基因敲除（KO）小鼠对MA的响应表现出增加的活性，我们表明，与野生型（WT）同窝仔相比，它们更喜欢消耗更多的MA。此外，表达非功能性TAAR1的KO小鼠和小鼠对MA的厌恶作用不敏感（体温过低，条件性味觉厌恶）。 TAAR1没有商业上可用的选择性激动剂或拮抗剂。开发出干扰TAAR1的MA介导作用的新药具有临床意义，因为（部分）激动剂可以作为可能限制MA摄入的治疗方法。相反，TAAR1拮抗剂可以作为进一步研究TAAR1介导的生理学的重要药物工具。该项目将使用一种翻译方法来表征培养的细胞，这些细胞表达人类TAAR1的多种非同义单核苷酸多态性（SNP）。此外，我们还将使用小鼠中人TAAR1多态性的病毒介导的基因转移来确定旨在影响人TAAR1功能并与MA竞争的合成新型剂的作用。这些实验的结果将确定TAAR1在MA介导的药理学和行为中的作用，并将表征我们实验室中合成的潜在新药物治疗，这些药物可用于治疗MA滥用和成瘾的特定症状。