Disentangling the biological links between violence and alcohol use

项目概要/摘要 酒精滥用通常与病理性攻击有关，这是一种经常性的破坏性和暴力行为模式。 行为尽管这一共同体的影响造成了重大的社会经济负担，但 有效的治疗是有限和不充分的。在治疗酒精滥用和 病理性攻击存在于这两个实体之间的复杂联系：一方面，酒精会使人感到不适， 暴力倾向的易感个体;另一方面，愤怒和侵略增加的风险， 饮酒解开这些疾病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，我们集中在最具特征的基因×环境（G×E） 病理性攻击和酒精使用的相互作用，发生在低活性等位基因之间， MAOA基因（编码单胺氧化酶A）和儿童虐待。我们最近开发了 这种G×E相互作用的第一个动物模型，通过使具有MAOA亚型突变的小鼠品系， 在出生后的第一周就有压力。 本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层和丘脑核的改变， 酗酒和暴力行为的恶性循环本提案的三个目标将侧重于：1） 这两个问题的共同神经发育机制; 2）饮酒的不良影响， 攻击性; 3）愤怒和社会反应对饮酒倾向的影响。综合起来看， 本研究将有助于阐明酒精滥用与病理性损害共病的机制， 锡永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.