Behavioral Neurobiology of Aggression

描述（由申请人提供）：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越来越多的证据，表明饮酒、冲动和病理性攻击之间存在联系。该研究旨在从行为和神经化学层面剖析这些联系，特别关注GABAA和血清素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与其他形式的升级攻击之间的关系。实验的目的是验证这样一种假设，即不同形式的升级攻击的共同行为特征是否具有酒精加剧攻击的个体特征。第二个和第三个目标集中在药理学工具上，用于表征5-HT1A、5-HT1B和GABAA受体的相对作用，它们在脑干和前额皮质区域的突触前和突触后位点，以及参与酒精增强攻击的动物。第四个目的是研究gaba能系统的血清素调节如何决定酒精增强的攻击性。相反，GABAA受体上的调节位点的神经药理学操作，特别是通过神经类固醇，如何使5- ht介导的攻击行为产生影响？药理学实验旨在刺激突触前5-HT1A和5-HT1B受体或神经毒性损伤中颚核，以评估5-羟色胺能抑制对神经类固醇等正性调节剂对酒精增强攻击的激活作用的重要性。第五个目标是针对gaba能和5 -羟色胺能机制的神经部位，这些机制对酒精的攻击性增强作用至关重要。颅内显微注射用于确定中隔核或前脑末端区域的5-羟色胺受体激活是否是减少升级战斗的关键部位。相反，阻断豚鼠体内的5-羟色胺自受体是否能增强酒精和其他正向调节剂对GABAA受体的攻击增强作用？进一步的证据将通过体内微透析实验获得，以了解行为改变是否反映在皮质边缘和脑干区域GABA和血清素释放水平的显著变化中。

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.