Behavioral Neurobiology of Aggression, Alcohol, GABA, and 5-HT

描述(申请人提供)：暴力爆发是酒精消费最昂贵、最可怕和最具破坏性的后果之一，是公共卫生和刑事司法系统最严重的问题之一。这项拟议的研究旨在增加我们对酒精导致某些人的攻击性行为升级的神经机制的理解，而对另一些人则不然。该提案侧重于与酒精有关的两类攻击，即急性酒精中毒后升级的攻击和间歇性戒酒期间的攻击。最重要的假设是评估攻击性升级，特别是在酒精影响下，如何成为CRF系统调节的两个神经回路失调的函数。(1)我们计划对表现为防御性的酒精戒断攻击行为进行功能性表征，并将其与自我注射低剂量酒精后的攻击增强效果进行对比，模拟与急性酒精中毒相关的暴力行为。(2)拟议的研究将检验这样一种假设，即在连续饮酒期间的戒酒间隔期间，焦虑症和防御性攻击是基于边缘前脑结构中CRF活性的增加，这反过来又改变了谷氨酸-GABA输入对单胺能通路的适应。相反，我们建议检验这样一种假设，即CRF-R1的拮抗作用调节了从中缝背核到前额叶皮质的上行5-羟色胺冲动流，从而减少了急性自我给予酒精的攻击刺激效应。(3)我们的目标是使用分子遗传学工具来描述间歇性饮酒和随后的戒断攻击过程中CRF和GABA受体系统的特征。我们将使用诱导敲除技术来确定杏仁核中GABAA受体亚型在酒精强化攻击和酒精戒断攻击中的相对重要性。实验工作依赖于定量行为学方法来分析物种标准和不断升级的攻击形式、自愿酒精自我给药、实时聚合酶链式反应、原位杂交组织化学、遗传操作、体内微透析和高效液相，以及脑内微量输注。预期结果将确定治疗干预的目标。

DESCRIPTION (provided by applicant): Violent outbursts are one of the most costly, horrifying and damaging consequences of alcohol consumption, representing one of the most significant problems for the public health and criminal justice systems. The proposed research aims to increase our understanding of the neural mechanisms via which alcohol escalates aggressive behavior in some individuals but not in others. The proposal focuses on two types of aggression that are related to alcohol, escalated aggression after acute alcohol intoxication and aggression during withdrawal from intermittently accessible alcohol. The overarching hypothesis is to assess how escalated aggression, particularly under the influence of alcohol, is a function of dysregulation of two neurocircuits that are modulated by the CRF system. (1) We plan to functionally characterize ethanol-withdrawal aggression which appears defensive in nature, and contrast it with the aggression-heightening effects that follow the self- administration of an acut low alcohol dose, modeling the violence associated with acute alcohol intoxication. (2) The proposed studies will test the hypothesis that dysphoria and defensive aggression during the abstinence interval between consecutive access periods to alcohol is based on increased CRF activity in limbic forebrain structures, which in turn alters the adaptations in glutamate - GABA inputs to monoaminergic pathways. By contrast, we propose to test the hypothesis that antagonism of CRF-R1 modulates ascending serotonin impulse flow from the dorsal raph¿ nucleus to the prefrontal cortex and thus reduces the aggression- stimulating effects of acutely self-administered alcohol. (3) We aim to use molecular genetic tools to characterize the CRF and GABA receptor systems during escalated intermittent alcohol drinking and during the ensuing withdrawal aggression. We will use inducible knock-down technology in order to define the relative importance of GABAA receptor subtypes in the amygdala in alcohol-heightened aggression and alcohol- withdrawal aggression. The experimental work relies on quantitative ethological methodology for the analysis of species-normative and escalated forms of aggression, voluntary alcohol self-administration, real time PCR, in situ hybridization histochemistry, genetic manipulations, in vivo microdialysis and HPLC, and intracerebral microinfusions. The anticipated outcome will identify targets for therapeutic interventions.