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

攻击行为、酒精、GABA 和 5-HT 的行为神经生物学

• 批准号: 8506142
• 负责人: KLAUS A MICZEK
• 金额: $ 32.16万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506142
• 关键词: Abstinence; Acute; Affect; Aggressive behavior; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Animals; Behavior; Behavioral; Brain; Brain region; CRF receptor type 1; Cell Nucleus; Complement; Consumption; Corticotropin-Releasing Hormone Receptors; Criminal Justice; Dependence; Dorsal; Dose; Eating; Equilibrium; Ethanol; Experimental Models; GABA Receptor; Glutamates; Health Personnel; High Pressure Liquid Chromatography; Histocytochemistry; Hour; In Situ Hybridization; Individual; Intake; Intoxication; Lead; Link; Mediating; Methodology; Microdialysis; Modeling; Molecular Genetics; Mus; Nature; Neurobiology; Neurotransmitters; Nucleus Accumbens; Obesity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Prefrontal Cortex; Prosencephalon; Protocols documentation; Public Health; Relative (related person); Research; Research Proposals; Role; Self Administration; Self-Administered; Serotonin; Social Behavior; Stressful Event; Structure; System; Technology; Testing; Therapeutic Intervention; Time; Violence; Water; Withdrawal; Work; alcohol availability; base; clinically relevant; conditioning; dorsal raphe nucleus; drinking; dysphoria; excessive behavior; gamma-Aminobutyric Acid; genetic manipulation; in vivo; indexing; knock-down; neuroadaptation; neuromechanism; preference; problem drinker; public health relevance; receptor; response; tool

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.

描述（由申请人提供）：暴力爆发是饮酒造成的最昂贵、最可怕和最具破坏性的后果之一，也是公共卫生和刑事司法系统面临的最重大问题之一。这项研究旨在加深我们对神经机制的理解，通过这种机制，酒精会加剧某些人的攻击性行为，而另一些人则不会。该提案重点关注与酒精相关的两种类型的攻击行为，即急性酒精中毒后升级的攻击行为和间歇性饮酒期间戒断期间的攻击行为。最重要的假设是评估攻击性的升级，特别是在酒精的影响下，是如何由 CRF 系统调节的两个神经回路失调引起的。 （1）我们计划从功能上表征本质上具有防御性的乙醇戒断攻击性，并将其与自我服用急性低剂量酒精后的攻击性增强效应进行对比，模拟与急性酒精中毒相关的暴力。 (2) 拟议的研究将检验以下假设：连续饮酒期间的戒酒间隔期间的烦躁和防御性攻击是基于边缘前脑结构中 CRF 活动的增加，这反过来又改变了谷氨酸 - GABA 输入对单胺能途径的适应。相比之下，我们建议检验以下假设：CRF-R1 的拮抗作用调节从中缝背核到前额皮质的上行血清素脉冲流，从而减少急性自我饮酒的攻击性刺激作用。 (3) 我们的目标是使用分子遗传学工具来表征间歇性饮酒升级和随后的戒断攻击期间的 CRF 和 GABA 受体系统。我们将使用诱导击倒技术来确定杏仁核中 GABAA 受体亚型在酒精增强攻击性和酒精戒断攻击性中的相对重要性。实验工作依赖于定量行为学方法来分析物种规范和升级形式的攻击、自愿酒精自我管理、实时PCR、原位杂交组织化学、基因操作、体内微透析和高效液相色谱以及脑内微量输注。预期结果将确定治疗干预的目标。