Disentangling the biological links between violence and alcohol use

解开暴力和酗酒之间的生物学联系

• 批准号: 10660813
• 负责人: Marco Bortolato
• 金额: $ 53.16万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660813
• 关键词: Acute; Adolescence; Adverse effects; Aggressive behavior; Alcohol consumption; Alcohols; Alleles; Anger; Animal Model; Animals; Behavioral; Biological; CRF receptor type 1; Child Abuse and Neglect; Clinical; Complex; Corticotropin-Releasing Hormone; Data; Development; Dopamine; Dose; Economic Burden; Electrophysiology (science); Enzymes; Female; Genes; Genetic Carriers; Genotype; Glutamate Receptor; Human; Impairment; Individual; Life; Link; Modeling; Monoamine Oxidase A; Mus; Mutation; N-Methylaspartate; Neurons; Nucleus Accumbens; Pathologic; Pattern; Prefrontal Cortex; Prevention; Process; Receptor Activation; Recording of previous events; Recurrence; Regimen; Research; Serotonin; Shapes; Signal Transduction; Slice; Testing; Time; Variant; Violence; alcohol abuse therapy; alcohol and other drug; alcohol comorbidity; alcohol effect; alcohol misuse; alcohol prevention; alcohol reinforcement; alcohol reward; alcohol risk; antagonist; comorbidity; conditioned place preference; drug of abuse; early life exposure; early life stress; economic impact; gene environment interaction; high risk; male; mutant; neurobiological mechanism; novel therapeutics; postnatal; preference; pup; receptor function; reinforced behavior; social; socioeconomics; transmission process

PROJECT SUMMARY/ABSTRACT Alcohol misuse is often associated with pathological aggression, a recurrent pattern of disruptive and violent behavior. Despite the significant socioeconomic burden imposed by the repercussions of this comorbidity, avail- able treatments are limited and inadequate. A critical problem in treating the association of alcohol misuse and pathological aggression lies in the complex links between these two entities: on the one hand, alcohol worsens violence propensity in predisposed individuals; on the other hand, anger and aggression increase the risk of alcohol use. Disentangling the links between these conditions is critical to developing better therapies. To study these neurobiological mechanisms, we focused on the best-characterized gene × environment (G×E) interaction underlying pathological aggression and alcohol use, occurring between low-activity alleles of the MAOA gene (encoding the enzyme monoamine oxidase A) and child maltreatment. We recently developed the first animal model of this G×E interaction by subjecting a line of mice with an MAOA hypomorphic mutation to early-life stress during the first week of life. The studies proposed in this application will test the hypothesis that the interaction of low-activity MAOA variants and child maltreatment leads to alterations of the prefrontal cortex and nucleus accumbens, which predispose to a vicious cycle of increased alcohol use and aggression. The three Aims of this proposal will focus on 1) the common neurodevelopmental mechanisms of these two problems; 2) the adverse effects of alcohol drinking on aggression; and 3) the impact of anger and social reactivity on the propensity to drink alcohol. Taken together, this research will help elucidate the mechanisms of the comorbidity of alcohol misuse and pathological aggres- sion and identify new potential targets for the prevention and treatment of alcohol-associated violence.

项目摘要/摘要 酒精遗产通常与病理侵略性有关，这是一种反复出现的破坏性和暴力模式 行为。尽管这种合并症的影响施加了重大的社会经济伯恩，但可用的 有限的治疗是有限的和不足的。治疗滥用酒精的关联和 病理侵略在于这两个实体之间的复杂联系：一方面，酒精恶化 易感人群的暴力倾向；另一方面，愤怒和激进增加了 饮酒。解开这些条件之间的联系对于开发更好的疗法至关重要。 为了研究这些神经生物学机制，我们专注于特征最佳的基因×环境（G×e） 在病理侵略和饮酒的基本相互作用，发生在低活动等位基因之间 MAOA基因（编码单胺氧化酶A）和儿童虐待。我们最近开发了 通过将MAOA型肌电突变的小鼠线施加给该G×E相互作用的第一个动物模型 生命第一周的早期压力。 本应用中提出的研究将检验以下假设：低活动性MAOA变体的相互作用 儿童虐待导致前额叶皮层和伏隔核的改变，这使得易感性 达到增加酒精饮酒和侵略性的奇妙循环。该提案的三个目标将重点放在1） 这两个问题的常见神经发育机制； 2）饮酒的不利影响 挑衅的; 3）愤怒和社会反应性对饮酒的承诺的影响。在一起， 这项研究将有助于阐明酒精滥用和病理促进性的合并症的机制。 sion并确定预防和治疗酒精相关暴力的新潜在目标。