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

攻击行为神经生物学：酒精、GABA 和 5-HT

• 批准号: 8308022
• 负责人: KLAUS A MICZEK
• 金额: $ 45.98万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308022
• 关键词: AMPA Receptors; Address; Aggressive behavior; Alcohol consumption; Alcohols; Animals; Autoreceptors; Behavior; Behavioral; Brain; Cells; Child Abuse; Corticotropin-Releasing Hormone Receptors; Crime; Criminal Justice; Data; Diagnostic; Dorsal; Epidemiology; Family; Feedback; GABA-A Receptor; Gene Expression; Genetic; Glutamate Receptor; Glutamates; Health; High Pressure Liquid Chromatography; Histocytochemistry; In Situ Hybridization; Individual; Individual Differences; Interneurons; Link; Mediator of activation protein; Metabotropic Glutamate Receptors; Methodology; Microdialysis; Minority; Mus; N-Methylaspartate; Neurobiology; Neurons; Outcome; Patients; Point Mutation; Population; Prefrontal Cortex; Presynaptic Receptors; Process; Public Health; Rattus; Relative (related person); Research; Research Proposals; Role; Self Administration; Serotonin; Signal Transduction; Source; Subgroup; System; Therapeutic Intervention; Time; Translating; Violence; Wife; Work; alcohol effect; assault; attenuation; base; brain metabolism; design; gamma-Aminobutyric Acid; in vivo; neuromechanism; presynaptic; receptor; research study; social; statistics; transmission process

DESCRIPTION (provided by applicant): The proposed research will increase our understanding of the neural mechanisms via which alcohol escalates aggressive behavior in some individuals but not in others. 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 overarching hypothesis is to assess how escalated aggression, particularly under the influence of alcohol, is a function of dysregulation of serotonergic activity in the raphe cells by feedback via somatodendritic autoreceptors and by GABAergic and glutamatergic influences, especially by feedback from the prefrontal cortex, and by CRF input. We propose that the dysregulation of feedback control on serotonergic neurons projecting to prelimbic, infralimbic and orbitoventral regions of the prefrontal cortex characterizes those individuals who engage in escalated aggressive behavior after alcohol consumption. Specifically, experiments in mice and rats are designed to answer the following questions: (1) How is the activity of serotonergic projections from the dorsal raphe n (DRN) to the prefrontal cortex (PFC) regulated in individuals who engage in escalated aggressive behavior? To which extent is the expression of 5-HT receptor subtypes in the prefrontal cortex critical for escalated aggressive behavior? Is gene expression for the 5-HT1 and 5-HT2 receptor families in the prefrontal cortex suppressed in animals that engage in alcohol-heightened aggression? What is the respective role of presynaptic receptors in the PFC terminals relative to somatodendritic autoreceptors and SERT in gating serotonin transmission in highly aggressive individuals, particularly after alcohol consumption? (2) Are glutamatergic and GABAergic influences on the 5-HT cells in the DRN critical for the display of escalated aggressive behavior, particularly after alcohol self-administration? Do these signals originate from GABAergic interneurons? How significant is the glutamatergic feedback from the PFC? Which subunits in GABA-A receptors are essential for the aggression- heightening effects of alcohol? Are NMDA glutamate receptor subtypes more selective in their modulation of escalated aggression after alcohol self-administration than AMPA receptors? (3) How critical is the modulation by CRF of serotonergic projections to the PFC in individuals who engage in escalated aggressive behavior? Can the respective role of CRF 1 and 2 receptor subtypes be defined for the intensification or attenuation of alcohol-heightened aggressive behavior? Are the CRF receptors on serotonergic cells the critical population that is pivotal for escalated aggressive behavior after alcohol self-administration? 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 point mutations, in vivo microdialysis and HPLC, and intracerebral microinfusions. The anticipated outcome will identify targets for therapeutic interventions. PUBLIC HEALTH RELEVANCE: The rationale for the proposed research is readily translated to one of the most significant problems for the public health and criminal justice system, namely to understand why alcohol escalates aggressive behavior in some individuals but not in others. Violent outbursts are one of the most costly, horrifying and destructive consequences of alcohol consumption. The proposed research will assess how escalated aggression, particularly under the influence of alcohol, is a function of dysregulation of serotonergic activity in the raphe cells by feedback via GABAergic, glutamatergic and CRF modulation.

描述（由申请人提供）：拟议的研究将增加我们对酒精在某些人中升级侵略性行为但在其他人中升级的神经机制的理解。暴力爆发是饮酒最昂贵，最恐怖和破坏的后果之一，这是公共卫生和刑事司法系统最重要的问题之一。总体假设是评估侵略性如何，尤其是在酒精的影响下如何通过通过体育跨性自身受体的反馈以及GABAERGIC和GABAERGIC和GLUTAMATAMATARGIC的影响，特别是受前期CORTEX和CRFFF FF FF FF FF FRF的反馈，这是通过反馈Raphe细胞中血清素能活性的函数。我们建议，前额叶皮层的反馈控制反馈控制对预测前，注射和眶外区域的血清素能神经元的失调，这是那些在饮酒后从事侵略性行为升级的人的表征。具体而言，在小鼠和大鼠中进行的实验旨在回答以下问题：（1）在从事升级积极行为的个人中，从背raphe n（DRN）到前额叶皮层（PFC）的血清素能投影的活动如何？前额叶皮层中5-HT受体亚型的表达对升级的攻击行为至关重要？前额叶皮层中5-HT1和5-HT2受体家族的基因表达是否在参与酒精高侵略的动物中抑制了？突触前受体在PFC终端中相对于体育体自身受体和SERT在高度攻击性个体中，尤其是在酒精消耗之后的门控羟色胺传播中的作用是什么？ （2）在DRN中，谷氨酸能和GABA能对5-HT细胞的影响是否对于表现出升级的攻击行为至关重要，尤其是在酒精自我管理之后？这些信号是否来自GABA能中间神经元？来自PFC的谷氨酸能反馈有多重要？ GABA-A受体中的哪些亚基对于侵略性提高酒精至关重要？ NMDA谷氨酸受体亚型比AMPA受体在调节酒精自我给药后的侵略性调节时更有选择性吗？ （3）CRF对PFC的CRF调节对从事侵略性行为升级的个体的调制对PFC有多关键？ CRF 1和2受体亚型的作用是否可以定义为酗酒侵略行为的加强或衰减？血清素能细胞上的CRF受体是否是饮酒自我管理后侵略行为升级的关键种群？实验性工作依赖于定量伦理学方法论，用于分析物种规范和升级形式的侵略性，自愿性醇自我给药，实时PCR，原位杂交组织化学，遗传点突变，体内微观透析和HPLC，以及脑脑内的微构型。预期的结果将确定治疗干预措施的目标。公共卫生相关性：拟议研究的基本原理很容易被转化为公共卫生和刑事司法系统最重要的问题之一，即了解为什么酒精在某些人中升级了侵略性行为，而不是在另一些人中升级。暴力爆发是饮酒最昂贵，最恐怖和破坏性的后果之一。拟议的研究将通过通过GABA能，谷氨酸能和CRF调节反馈来评估侵略性的侵略，特别是在酒精的影响下如何升级侵略性。