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: 9032402
• 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/9032402
• 关键词: Affect; Agonist; Alleles; American; Amines; Animal Behavior; Behavior; Behavioral; Brain; Breeding; 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; addiction; analog; cost; design; drinking; genetic variant; in vivo; methamphetamine abuse; methamphetamine effect; methamphetamine exposure; methamphetamine use; natural hypothermia; novel; novel therapeutics; patient population; public health relevance; receptor; research study; response; 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）： 兰德公司最近的一项研究表明，滥用甲基安非他明每年给美国造成200亿至600亿美元的损失。大约有1000万美国人至少使用过一次MA。长期使用MA具有深远的健康后果和巨大的社会影响。在退伍军人管理局。医疗中心MA滥用与设施资源的使用增加和对退伍军人的有害后果有关，例如额外的精神疾病。目前没有批准的药物用于治疗MA成瘾，因此迫切需要发现MA药物疗法。最近，痕量胺相关受体1（TAAR 1）已被确定为MA及其类似物的靶点，但不是可卡因的靶点。因此，TAAR 1可能是唯一的MA靶标。TAAR1基因敲除（KO）小鼠显示出对MA的反应活性增加，我们已经表明，与野生型（wt）同窝仔相比，它们优先消耗更多的MA。此外，KO小鼠和表达非功能性TAAR 1的小鼠对MA的厌恶效应（体温过低、条件性味觉厌恶）不敏感。没有市售的TAAR 1的选择性激动剂或拮抗剂。开发干扰MA介导的TAAR 1效应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拮抗剂可以作为重要的药理学工具，以进一步研究TAAR1介导的生理学。该项目将使用翻译方法来表征表达人TAAR 1的多个非同义单核苷酸多态性（SNP）的培养细胞。此外，我们将在小鼠中使用病毒介导的人类TAAR 1多态性基因转移来确定设计用于影响人类TAAR 1功能并与MA竞争的合成新药物的效果。这些实验的结果将确定TAAR 1在MA介导的药理学和行为中的作用，并将表征我们实验室合成的潜在新药物疗法，这些药物疗法可用于治疗MA滥用和成瘾的特定症状。