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危险因素之一， 越来越多的人对此类病例的遗传和表观遗传基础仍知之甚少。 有证据表明，许多滥用药物，例如安非他明或可卡因，会诱发 然而，尚无研究表明药物暴露后短暂出现的基因表达变化。 迄今为止已经进行了阐明重复给药可以产生的影响 由于吸毒成瘾是一种高度遗传的疾病，因此它会遗传给后代。 至关重要的是检查滥用药物诱导的基因表达是否同样如此 可遗传给后代。这将涉及稳定的表观遗传修饰。 后代会持续存在，成瘾会影响脆弱性。 该拨款提案的中心目标是调查跨代影响 特别是，我们研究了多巴胺能突触的安非他命。 安非他明对多巴胺转运蛋白和多巴胺受体的影响是因为 这些蛋白质是苯丙胺和可卡因等滥用药物的重要目标，并且 我们通过触发表观遗传来捕捉到这一点。 负责调节大脑反应的基因和通路的变化 安非他明，与这种精神兴奋剂相关的行为和生理变化 我们的建议是研究表观遗传变化。 由安非他明引起并遗传给后代（目标 2），包括 对安非他明如何改变关键参与者的活动进行彻底的功能调查 重要的是，因为表观遗传机制是动态的。 并且是可逆的，我们还设计了一个计划，测试药物干预是否有效 特异性抑制表观遗传修饰药物，防止跨代效应 由安非他明诱导（目标 3）。