Disentangling the biological links between violence and alcohol use

项目摘要/摘要 酒精滥用通常与病理性攻击有关，这是一种反复出现的破坏性和暴力模式。 行为。尽管这种共病的影响造成了巨大的社会经济负担，但有益的是- 有能力的治疗是有限的和不充分的。处理酒精滥用和酒精滥用之间的关系的一个关键问题 病理性攻击存在于这两个实体之间的复杂联系中：一方面，酒精会恶化 易感个体的暴力倾向；另一方面，愤怒和攻击性增加了 酗酒。弄清这些疾病之间的联系对于开发更好的治疗方法至关重要。 为了研究这些神经生物学机制，我们重点研究了特征最好的基因×环境(G×E) 病理性攻击和饮酒之间的相互作用，发生在低活性等位基因之间 MAOA基因(编码单胺氧化酶A)与儿童虐待我们最近开发了 第一个这种G×E相互作用的动物模型是通过使一组带有MAOA亚型突变的小鼠 在生命的第一周，生命早期的压力。 在这项申请中提出的研究将检验低活性MAOA变体的相互作用 虐待儿童会导致前额叶皮质和伏隔核的改变，这是容易发生的 酿成酗酒和攻击性增加的恶性循环。这项建议的三个目标将集中在1) 这两个问题的共同神经发育机制；2)饮酒对 攻击性；以及3)愤怒和社会反应对饮酒倾向的影响。加在一起， 这项研究将有助于阐明酒精滥用与病理性攻击并存的机制。 Sion，并确定预防和治疗与酒精有关的暴力的新的潜在目标。

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.