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: 10427124
• 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/10427124
• 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; Methamphetamine use disorder; Modeling; Mood Disorders; Moods; Mus; Mutation; Neurotoxins; New York; Oregon; Other Genetics; Overdose; Paranoia; Pattern; Persons; Phenotype; Physiological; Policies; Population; Post-Traumatic Stress Disorders; Prevention; Production; Relapse; Research; Resistance; Rewards; Risk; Role; Saline; Single Nucleotide Polymorphism; Stimulant; 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; gene network; 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.

甲基苯丙胺（MA）使用可以改变判断力，增加不安全的行为和暴力，并引起情绪 干扰。长期使用与偏执狂以及视觉和听觉幻觉有关。一个 指标的数量指出了美国的可用性和滥用量的增加，尤其是在美国 南部和西部地区，包括年轻人和老年人。 MA通常是在重复的狂欢中获取的 水平剂量和沉迷于MA的个人即使延长了 节制时期。当服用较高量时，MA是一种神经毒素。风险作为人口量度 在没有通过多种策略暴露药物的情况下，可以在动物模型中评估 包括使用有选择的繁殖动物线。理查兹实验室已经开发了动物模型 狂饮样的MA摄入量以研究遗传风险，神经毒性和MA行为影响的变化 与这种高水平的摄入量有关。该模型与对MA的抗药性的遗传模型一致 在理查兹实验室中也开发的摄入量用于鉴定痕量胺相关受体1 （TAAR1）作为一种基因，占MA摄入中遗传方差的50％。高风险等位基因代码 用于接收器的非功能版本。但是，尽管在等生背景中，taar1等位基因 类型占表型差异的92％，仅占A的表型差异的68％ 混合遗传背景。此外，一些纯合为高风险TAAR1的人 等位基因保留低MA摄入量。除了检查与暴饮暴食水平MA相关的神经毒性 暴露和差异TAAR1基因型，该研究计划的重点将放在识别上 通过转录组分析，可以防止个体的暴饮暴食级摄入量的机制 已知具有高风险的TAAR1基因型；换句话说，可以识别遗传修饰符。在AIM 1中， 将比较受控的暴饮暴食水平剂量和自愿性暴饮暴食水平的MA摄入量的神经毒性 在高Ma摄入选定的小鼠系和高MA进气线的小鼠中的效果，其中TAAR1 促进高Ma摄入量的等位基因已被保护等位基因取代，这是一种遗传敲击 方法。在AIM 2中，自愿狂欢级别的MA摄入量对条件奖励和可靠的影响 将检查对MA的生理反应 - 体温变化 - 将被检查。在AIM 3中，一个新的通用 将开发模型的双向选择的线，这些线从个人中 TAAR1 MA风险等位基因的纯合子，但为高Ma摄入量而繁殖。虽然被列为AIM 3，但 这些行的生产将在研究计划的早期开始，以便可以使用它们 3年级。这些线也将以MA奖励，温度变化，味道偏好和 MA清除率。最后，在AIM 4中，将使用从选定线到的组织进行分析 确定预测TAAR1等位基因对MA摄入效果的衰减的转录组中的差异。 将使用来自盐水和MA处理的动物的组织。因为有人类taar1的证据 影响接收器功能的等位基因差异，这是一个令人兴奋的研究方向，可能导致 鉴定保护性因素，这些因素减轻了暴饮暴食水平的遗传风险，并最终识别 以及更有效的治疗方法。

项目成果

Methamphetamine Consumption Inhibits Pair Bonding and Hypothalamic Oxytocin in Prairie Voles.

• DOI: 10.1371/journal.pone.0158178
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hostetler CM;Phillips TJ;Ryabinin AE
• 通讯作者: Ryabinin AE

Peri-adolescent exposure to (meth)amphetamine in animal models.

• DOI: 10.1016/bs.irn.2021.06.011
• 发表时间: 2022
• 期刊: INTERNATIONAL REVIEW OF NEUROBIOLOGY
• 作者: Phillips, T. J.;Aldrich, S. J.
• 通讯作者: Aldrich, S. J.

Prefrontal glutamate correlates of methamphetamine sensitization and preference.

• DOI: 10.1111/ejn.13159
• 发表时间: 2016-03
• 期刊: The European journal of neuroscience
• 作者: Lominac KD;Quadir SG;Barrett HM;McKenna CL;Schwartz LM;Ruiz PN;Wroten MG;Campbell RR;Miller BW;Holloway JJ;Travis KO;Rajasekar G;Maliniak D;Thompson AB;Urman LE;Kippin TE;Phillips TJ;Szumlinski KK
• 通讯作者: Szumlinski KK

Long-term effects of exposure to methamphetamine in adolescent rats.

青少年大鼠暴露于甲基苯丙胺的长期影响。

• DOI: 10.1016/j.drugalcdep.2014.02.021
• 发表时间: 2014
• 期刊: Drug and alcohol dependence
• 影响因子: 4.2
• 作者: Ye,Tony;Pozos,Hilda;Phillips,TamaraJ;Izquierdo,Alicia
• 通讯作者: Izquierdo,Alicia

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.

• DOI: 10.1016/j.biopsych.2016.10.005
• 发表时间: 2017-06-01
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Szumlinski KK;Lominac KD;Campbell RR;Cohen M;Fultz EK;Brown CN;Miller BW;Quadir SG;Martin D;Thompson AB;von Jonquieres G;Klugmann M;Phillips TJ;Kippin TE
• 通讯作者: Kippin TE