Behavioral Neurobiology of Aggression

描述(申请人提供)：流行病学和犯罪统计以及神经生物学和药物治疗都提供了一致的证据，表明饮酒、冲动和病理性攻击之间的联系。这项拟议的研究旨在从行为和神经化学水平上剖析这些联系，特别关注GABAA和5-羟色胺系统之间的相对作用和相互作用。第一个具体目标是分析酒精加剧的攻击行为与其他形式的升级攻击行为之间的关系。实验旨在检验这一假设，即不同形式的不断升级的攻击性的共同行为特征是否表现出参与酒精强化攻击性的人的特征。第二和第三个目标集中在药理学工具上，这些工具被用来表征5-HT1A、5-HT1B和GABAA受体的相对贡献，它们在脑干中的突触前和突触后位置，以及参与酒精强化攻击的动物的前额叶皮质区域。第四个目的是研究GABA能系统的5-羟色胺能调节如何决定酒精增强的攻击性。相反，神经药理学如何操纵GABAA受体上的调节位点，特别是通过神经类固醇，使5-羟色胺对攻击行为产生影响？药理学实验的目的是刺激突触前的5-HT1A和5-HT1B受体或对中缝核团进行神经毒性损伤，以评估5-羟色胺能抑制对神经类固醇等正向调节剂在酒精增强的攻击行为中激活作用的重要性。第五个目标是针对GABA能和5-羟色胺能机制的神经部位，这两种机制对酒精的攻击增强效应至关重要。颅内微量注射被用来确定中缝核内或前脑末端区域的5-羟色胺受体的激活是否是减少不断升级的战斗的关键部位。相反，阻断中缝核内的5-羟色胺自身受体能增强酒精和其他正向调节剂对GABAA受体的攻击增强作用吗？通过体内微透析实验将获得更多证据，以了解行为变化是否反映在皮质边缘和脑干区域GABA水平和5-羟色胺释放的显著变化中。

DESCRIPTION (provided by applicant): Epidemiological and criminal statistics as well as neurobiology, and pharmacotherapy all provide converging evidence that suggests links between alcohol consumption, impulsivity, and pathological aggression. The proposed research aims to dissect these links at the behavioral and neurochemical level, with particular focus on the relative role and interactions between GABAA and serotonin systems. A first specific aim seeks to analyze how alcohol-heightened aggression is related to other forms of escalated aggression. Experiments are designed to test the hypothesis whether or not a common behavioral profile of varied forms of escalated aggression characterizes individuals who engage in alcohol-heightened aggression. The second and third aims focus on pharmacological tools that are employed to characterize the relative contribution of 5-HT1A, 5-HT1B, and GABAA receptors, their pre- versus post-synaptic sites in brainstem, and prefrontal cortical regions in animals that engage in alcohol-heightened aggression. The fourth aim examines how serotonergic modulation of GABAergic systems determines alcohol-heightened aggression. Inversely, how do neuropharmacological manipulations of the modulatory sites on the GABAA receptor, particularly via neurosteroids, enable 5-HT-mediated effects on aggressive behavior? Pharmacological experiments are designed to stimulate pre-synaptically 5-HT1A and 5-HT1B receptors or to neurotoxically lesion raphe nuclei in order to assess the importance of serotonergic inhibition on the activating effects of positive modulators like neurosteroids on alcohol-heightened aggression. A fifth aim is directed at the neural sites of the GABAergic and serotonergic mechanisms that are critical for the aggression-heightening effects of alcohol. Intracranial microinjections are used to determine whether activation of 5-HT receptors in the raphe nucleus or in terminal forebrain regions are the critical sites for reducing escalated fighting. Conversely, can blockade of the 5-HT autoreceptors in the raphe n. potentiate the aggression-heightening effects of alcohol and other positive modulators at GABAA receptors? Additional evidence will be obtained by in vivo microdialysis experiments, in order to learn whether behavioral changes are reflected in significant changes in the level of GABA and serotonin release in cortico-limbic and brainstem areas.