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).

虽然家族史是吸毒成瘾的最大风险因素之一，但 这些疾病的遗传和表观遗传基础仍然知之甚少。不断增长的 有证据表明，许多滥用药物，如安非他明或可卡因，会导致 药物暴露后出现的短暂的基因表达变化。然而，没有一项研究 到目前为止已经阐明了重复给药的影响 在后续世代中生成。因为毒瘾是一种高度可遗传的疾病，它是 研究滥用药物引起的基因表达变化是否同样 可以传给子孙后代。这将涉及稳定的表观遗传修饰，这 在后代身上坚持下去，并影响成瘾的脆弱性。 这项赠款提案的中心目标是调查 安非他明在多巴胺能突触。特别是，我们研究了跨代人 苯丙胺对多巴胺转运体和多巴胺受体的影响 这些蛋白质是安非他明和可卡因等滥用药物的重要靶点，并且 奖励途径的核心关键人物。我们假设通过触发表观遗传 负责调节大脑反应的基因和通路的变化 与这种精神刺激剂有关的苯丙胺、行为和生理变化是 代代相传。我们的建议是研究表观遗传学的变化 由代代相传的苯丙胺诱导(目标2)，包括 对安非他命如何改变主要参与者的活动进行彻底的功能调查 子代的多巴胺能系统(目标1)。重要的是，表观遗传机制是动态的 可逆的，我们还设计了一个计划，在这个计划中，我们测试药物干预， 抑制表观遗传修饰的特定药物，防止跨代效应 安非他明诱导(目标3)。