Dorsal Raphe Nucleus Serotonergic Neurons in Alcoholism

酒精中毒中的中缝背核血清素能神经元

• 批准号: 6879990
• 负责人: MARK D UNDERWOOD
• 金额: $ 30.19万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879990
• 关键词: alcoholism /alcohol abuse; brain mapping; clinical research; dorsal raphe nucleus; histopathology; human subject; human tissue; interview; neuropathology; neurotoxicology; neurotransmitter metabolism; neurotransmitter transport; postmortem; serotonin; serotonin inhibitor; serotonin transporter

EXCEED THE SPACE PROVIDED. Serotonin abnormalities in the brainstem and cerebral cortex of alcoholics is hypothesized based on reports of reduced serotonin metabolites inthe cerebrospinal fluid, the efficacyof serotonin agonists and uptake inhibitors in reducingalcoholconsumption inhumansandanimal models andbiochemical abnormalities inalcohol preferring rat strains. During the funded period considerable progress was made and postmortem evidence of alterations in serotonin-synthesizing neurons in the dorsal raphe nucleus (DRN) of alcoholics, including increased densityof neuronal processes, was obtained. In the prefrontal cortex, serotonin receptors were not markedly changed in alcoholics compared to matched controls. A novel immunoautoradiographic method was developed for quantifying tryptophan hydroxylase in frozen brainstem sections. A comprehensive series of postmortem studies of the serotonin system in frozen brainstem and forebrain is proposed to further examine serotonin source neurons in the DRN and target neurons in the lateral and orbital prefrontal cortex and in the anterior cingulate. The brain of 20 matched (age, sex, race, postmortem interval) pairs of cases with DSM-IV criteria for alcoho abuse or dependence and nonpsychiatric controlswill beexamined. Alcohol abuse/dependence will be diagnosed accordingto DSM-IV criteria bypsychological autopsy. Inthe DRN: tryptophan hydroxylase will be measured using immunoautoradiography at the level of the entire DRN (autoradiography) and in individual neurons (emulsion); in adjacent sections, 5-HT, precursors and metabolites will be measured in DRN punches (HPLC), and Serotonin transporter (SERT) sites and 5-HT1A autoreceptor binding in the DRN will be measured by quantitative autoradiography. In the ventrolateral and orbital prefrontal cortex, anterior cingulate and primary motor cortex, measurement of cortical neuron density will be determined using stereology and neuron density will be related to the concentration of serotonin transporter sites, 5-HT1Aand 5-HT2A receptors in the same cortical regionstoderive an index of the concentration of receptors per neuron. The studies are designed to assess the integrity of DRNserotonin neurons and neurons in the prefrontalcortex in alcoholics. The results of the studies should help to clarify whether serotonin receptors or neurons regulate or fail to regulate in alcoholics. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。 基于脑脊液中5-羟色胺代谢物减少、5-羟色胺激动剂和摄取抑制剂在人类和动物模型中减少酒精消耗的效果以及酒精偏好大鼠品系的生化异常的报道，推测酗酒者脑干和大脑皮质中5-羟色胺异常。在资助期间，取得了相当大的进展，并获得了酗酒者中缝背核（DRN）中合成胡萝卜素的神经元发生改变的死后证据，包括神经元过程的密度增加。在前额叶皮层，与对照组相比，酗酒者的5-羟色胺受体没有明显变化。建立了脑干冰冻切片中色氨酸羟化酶的免疫放射自显影定量方法。一个全面的系列死后研究的5-羟色胺系统在冷冻脑干和前脑，建议进一步研究5-羟色胺源神经元的DRN和目标神经元的外侧和眶前额叶皮层和前扣带。 将对20对符合DSM-IV酒精滥用或依赖标准的配对病例（年龄、性别、种族、死后时间）和非精神病对照组的大脑进行检查。酒精滥用/依赖将根据DSM-IV标准通过心理尸检进行诊断。在DRN中：色氨酸羟化酶将使用免疫放射自显影法在整个DRN（放射自显影法）和单个神经元（乳剂）的水平上进行测量;在相邻切片中，5-HT、前体和代谢物将在DRN穿孔（HPLC）中进行测量，5-羟色胺转运蛋白（SERT）位点和DRN中的5-HT 1A自身受体结合将通过定量放射自显影法进行测量。在腹外侧和眶前额叶皮质、前扣带和初级运动皮质中，将使用体视学测定皮质神经元密度，并且神经元密度将与相同皮质区域中5-羟色胺转运体位点、5-HT 1A和5-HT 2A受体的浓度相关，以获得每个神经元的受体浓度指数。 这些研究旨在评估酗酒者DRN 5-羟色胺神经元和前额叶皮层神经元的完整性。这些研究的结果应该有助于澄清在酗酒者中，5-羟色胺受体或神经元是否起调节作用。性能现场=