Genetic basis and mechanisms underlying binge-level methamphetamine intake

暴食水平甲基苯丙胺摄入的遗传基础和机制

• 批准号: 10082416
• 负责人: TAMARA J. RICHARDS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082416
• 关键词: Abstinence; Address; Alleles; Amines; Animal Genetics; Animal Model; Animals; Attenuated; Auditory Hallucination; Behavior; Behavioral; Body Temperature; Body Temperature Changes; Brain; Caring; Cessation of life; Chemicals; Chronic; Code; Consumption; Data; Diagnosis; Disease; Dose; Drug Controls; Drug Exposure; Elderly; Euphoria; Exhibits; Frequencies; Funding; Genes; Genetic; Genetic Models; Genetic Risk; Genetic study; Genotype; Goals; Heroin; Human; Illicit Drugs; Individual; Intake; Judgment; Knock-in; Laboratories; Lead; Measures; Medical; Medical center; Metabolic Clearance Rate; Methamphetamine; Modeling; Mood Disorders; Moods; Mus; Mutation; Neurotoxins; New York; Oregon; Other Genetics; Overdose; Paranoia; Pattern; Phenotype; Physiological; Policies; Population; Post-Traumatic Stress Disorders; Prevention; Production; Relapse; Research; Resistance; Rewards; Risk; Role; Saline; Single Nucleotide Polymorphism; Temperature; Time; Tissues; Toxic effect; United States; United States Department of Veterans Affairs; Variant; Veterans; Violence; Visual Hallucination; affective disturbance; alcohol use disorder; attenuation; drinking; effective intervention; effective therapy; genetic risk factor; high risk; inpatient service; insight; methamphetamine abuse; methamphetamine effect; methamphetamine exposure; methamphetamine use; mouse model; neurotoxic; neurotoxicity; post-traumatic stress; preference; programs; protective allele; protective factors; receptor; receptor function; relating to nervous system; response; risk variant; stimulant use; trait; transcriptome; transcriptome sequencing; young adult

Methamphetamine (MA) use can alter judgment, increase unsafe behaviors and violence, and cause mood disturbances. Chronic use is associated with paranoia, as well as visual and auditory hallucinations. A number of indicators point to increasing availability and abuse of MA in the United States, especially in the southern and western regions, among both young and older adults. MA is often taken in repeated binge- level doses, and individuals who become addicted to MA suffer high rates of relapse, even after prolonged periods of abstinence. MA is a neurotoxin when higher amounts are taken. Risk as a population measure can be assessed in animal models in the absence of drug exposure through a number of strategies, including the use of selectively bred animal lines. The Richards laboratory has developed an animal model of binge-like MA intake to study genetic risk, neurotoxicity, and changes in behavioral effects of MA associated with this high level of intake. That model, in concert with a genetic model of resistance to MA intake that was also developed in the Richards lab, was used to identify trace amine-associated receptor 1 (Taar1) as a gene that accounts for >50% of the genetic variance in MA intake. The high risk allele codes for a non-functional version of the receptor. However, whereas on an isogenic background, Taar1 allele type accounts for 92% of the phenotypic variance, it accounts for only 68% of the phenotypic variance on a mixed genetic background. Furthermore, some individuals that are homozygous for the high risk Taar1 allele retain a low MA intake profile. In addition to examining neurotoxicity associated with binge-level MA exposure and with differential Taar1 genotype, a focus of this research program will be on the identification of mechanisms, through transcriptome analyses, that protect against binge-level MA intake in individuals known to possess a high-risk Taar1 genotype; in other words to identify genetic modifiers. In Aim 1, controlled binge-level MA dosing and voluntary binge-level MA intake will be compared for their neurotoxic effects in a high MA intake selected mouse line and in mice of the high MA intake line in which the Taar1 allele that promotes high MA intake has been replaced with the protective allele, a genetic knock-in approach. In Aim 2, the impact of voluntary binge-level MA intake on conditioned-reward and a reliable physiological response to MA – body temperature change – will be examined. In Aim 3, a new genetic model will be developed comprised of bidirectionally selected lines derived from individuals that are all homozygous for the Taar1 MA risk allele, but are bred for high vs. low MA intake. Although listed as Aim 3, the production of these lines will begin early in the research program so that they are available for use by year 3. These lines will also be characterized for MA reward, temperature change, tastant preference and MA clearance rate. Finally, in Aim 4, analyses will be conducted using tissues from the selected lines to identify differences in the transcriptome that predict an attenuation of the Taar1 allele effect on MA intake. Tissues from saline- and MA-treated animals will be used. Because there is evidence for human TAAR1 allelic differences that impact receptor function, this is an exciting research direction that could lead to the identification of protective factors that alleviate genetic risk for binge-level MA intake and ultimately to new and more effective treatments.

使用甲基苯丙胺 (MA) 会改变判断力、增加不安全行为和暴力，并导致情绪低落 长期使用与偏执以及幻视和幻听有关。 大量指标表明，MA 在美国的可用性和滥用程度不断增加，特别是在 南部和西部地区的年轻人和老年人经常反复服用MA。 水平剂量，并且对 MA 成瘾的个体即使在长期服用后，复发率也很高。 当服用较高剂量的 MA 时，MA 是一种神经毒素。 可以在没有药物暴露的情况下通过多种策略在动物模型中进行评估， 包括使用选择性培育的动物系开发了一种动物模型。 狂饮 MA 摄入量，以研究 MA 的遗传风险、神经毒性和行为影响的变化 与这种高水平的摄入量有关，与 MA 抗性的遗传模型相一致。 Richards 实验室也开发了摄入量，用于识别痕量胺相关受体 1 (Taar1) 作为一个基因，占 MA 摄入量遗传变异的 50% 以上 高风险等位基因编码。 然而，在同基因背景下，Taar1 等位基因。 类型占表型变异的 92%，而仅占表型变异的 68% 此外，一些个体具有高风险 Taar1 纯合子。 除了检查与暴食水平 MA 相关的神经毒性外，等位基因还保留低 MA 摄入量。 暴露并具有差异 Taar1 基因型，该研究计划的重点将是鉴定 通过转录组分析，了解防止个体暴食水平 MA 摄入的机制 已知具有高风险 Taar1 基因型；换句话说，在目标 1 中识别遗传修饰因子。 将比较受控暴饮水平 MA 剂量和自愿暴饮水平 MA 摄入的神经毒性 对高 MA 摄入量的选定小鼠品系和高 MA 摄入量品系的小鼠的影响，其中 Taar1 促进高 MA 摄入量的等位基因已被保护性等位基因（一种基因敲入）所取代 在目标 2 中，自愿摄入 MA 水平对条件奖励和可靠的影响。 在目标 3 中，将检查对 MA 的生理反应（体温变化）。 模型将由来自个体的双向选择线组成，这些线都是 Taar1 MA 风险等位基因纯合，但针对高 MA 摄入量和低 MA 摄入量进行培育，尽管被列为目标 3， 这些生产线的生产将在研究计划的早期开始，以便可供 第 3 年。这些品系还将针对 MA 奖励、温度变化、味觉偏好和 最后，在目标 4 中，将使用选定品系的组织进行分析 确定转录组中的差异，预测 Taar1 等位基因对 MA 摄入量的影响减弱。 将使用来自经盐水和 MA 处理的动物的组织，因为有证据表明存在人类 TAAR1。 影响受体功能的等位基因差异，这是一个令人兴奋的研究方向，可能会导致 识别保护因素，减轻暴食水平 MA 摄入的遗传风险，并最终降低新的风险 以及更有效的治疗方法。