Amphetamine causes transgenerational effects

安非他明引起跨代效应

• 批准号: 9160562
• 负责人: Lucia Carvelli
• 金额: $ 31.28万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9160562
• 关键词: Ablation; Addictive Behavior; Adult; Affect; Amphetamines; Animals; Antibodies; Applications Grants; Behavior; Behavioral; Biological Markers; Brain; Caenorhabditis elegans; ChIP-seq; Chemical Agents; Chronic Disease; Cocaine; Data; Development; Dopamine Receptor; Drug Addiction; Drug Exposure; Elements; Enzymes; Epigenetic Process; Eukaryota; Exhibits; Exposure to; Family; Future Generations; Gene Expression; Generations; Genes; Genetic; Genetic Predisposition to Disease; Goals; Histones; Hypersensitivity; Inheritance Patterns; Inherited; Intervention; Investigation; Knock-out; Knowledge; Life Cycle Stages; Long-Term Effects; Lysine; Maintenance; Mammals; Measures; Mediating; Mediation; Mental disorders; Methylation; Modification; Molecular; Mutation; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Preventive Intervention; Proteins; Recording of previous events; Rewards; Risk Factors; Structure; Synapses; Synaptic plasticity; System; Testing; Therapeutic Intervention; Time; Tyrosine 3-Monooxygenase; Work; addiction; base; behavioral response; chromatin modification; demethylation; design; disease diagnosis; dopamine system; dopamine transporter; drug of abuse; epigenetic marker; epigenetic regulation; epigenome; epigenomics; gain of function; genome-wide; histone methylation; histone modification; in vivo; mature animal; methylation pattern; next generation sequencing; novel; offspring; prevent; promoter; psychostimulant; receptor; research study; response; transcriptome sequencing; transgenerational epigenetic inheritance; transmission process

Although family history represents one of the greatest risk factors for drug addiction, the genetic and epigenetic basis for such illnesses remains poorly understood. A growing body of evidence indicates that many drugs of abuse, such as amphetamine or cocaine, induce alterations in gene expression which appear transiently after drug exposure. However, no study has been conducted so far elucidating the effects that repeated drug administration can generate in subsequent generations. Because drug addiction is a highly heritable illness, it is crucial to examine whether altered gene expressions induced by drugs of abuse are likewise transmittable to future generations. This would involve stable, epigenetic modifications, which persist in offspring and affect addiction vulnerability. The central goal of this grant proposal is to investigate the trans-generational effects of amphetamine at the dopaminergic synapses. Particularly, we investigate the transgenerational effects amphetamine causes at the dopamine transporter and dopamine receptors because these proteins are important targets of drugs of abuse such amphetamine and cocaine, and are central key players of the reward pathway. We hypothesize that by triggering epigenetic changes in the genes and pathways responsible for mediating the brain’s response to amphetamine, behavioral and physiological changes associated with this psychostimulant are passed down to subsequent generations. Our proposal investigate the epigenetic changes induced by amphetamine that are passed through subsequent generations (Aim 2) and includes a thorough functional investigation of how amphetamine alters the activity of key players of the dopaminergic system in progeny (Aim 1). Importantly, as epigenetic mechanisms are dynamic and reversible, we also designed a plan in which we test if pharmacological intervention, with specific drugs that inhibit epigenetic modifications, prevents the transgenerational effects induced by amphetamine (Aim 3).

尽管家族史是吸毒成瘾的最大风险因素之一，但 这种疾病的遗传和表观遗传基础仍然对此知之甚少。越来越多的身体 证据表明，许多滥用药物（例如苯丙胺或可卡因）诱导 药物暴露后瞬时出现的基因表达改变。但是，没有研究 到目前为止已经阐明了重复药物可以的影响 生成后代。因为吸毒成瘾是一种高度遗传的疾病，所以 对于研究滥用药物引起的基因表达是否改变的至关重要 可传输到子孙后代。这将涉及稳定的表观遗传修饰，这 坚持后代并影响成瘾脆弱性。 该赠款提案的核心目标是研究 多巴胺能突触的苯丙胺。特别是我们研究了变革 在多巴胺转运蛋白和多巴胺接收器上对苯丙胺的作用，因为 这些蛋白质是滥用药物的重要靶标，例如苯丙胺和可卡因，是 奖励途径的主要主要参与者。我们通过触发表观遗传来假设这一点 导致大脑对大脑反应的基因和途径的变化 苯丙胺，与这种心理刺激剂相关的行为和身体变化是 传给了后代。我们的建议调查表观遗传变化 由苯丙胺诱导的，这些世代通过了（AIM 2），包括 苯丙胺如何改变主要参与者的活动的全面功能投资 多巴胺能系统正在进行中（AIM 1）。重要的是，由于表观遗传机制是动态的 可逆的，我们还设计了一个计划，在该计划中，我们测试了药物干预是否与 抑制表观遗传修饰的特定药物可以防止转化效应 由苯丙胺诱导（AIM 3）。