Dorsal Raphe Nucleus Serotonin Neurons in Alcoholism

酒精中毒中中缝背核血清素神经元

• 批准号: 8282371
• 负责人: MARK D UNDERWOOD
• 金额: $ 7.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282371
• 关键词: Activities of Daily Living; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anterior; Area; Autopsy; Autoreceptors; Behavior; Behavioral inhibition; Binding; Biochemical; Biological; Brain; Brain Stem; Brain imaging; Brain-Derived Neurotrophic Factor; Brodmann' s area; Cereals; Cerebral cortex; Cerebrospinal Fluid; Cessation of life; Collection; Communication; Computer Assisted; DSM-IV; Data; Dependence; Development; Diagnosis; Disease; Drug usage; Enzymes; Equilibrium; Family; Family history of; Follow-Up Studies; Funding; Gene Expression; Glutamate Decarboxylase; Glutamates; HTR2A gene; Health; Human; Image Analysis; In Situ Hybridization; Individual; Interneurons; Label; Maintenance; Measures; Medical; Messenger RNA; Methods; Molecular; Moods; Morphology; Neurons; Neurotransmitters; Pathogenesis; Phenotype; Predisposing Factor; Predisposition; Prefrontal Cortex; Preventive; Process; Proteins; Rat Strains; Recording of previous events; Relative (related person); Reporting; Serotonin; Serotonin Agonists; Serotonin Receptor 5-HT1A; Silver; Source; Staining method; Stains; System; TDO2 gene; Therapeutic; Tissues; Transcript; Tryptophan 5-monooxygenase; United States; Up-Regulation; alcohol effect; alcohol exposure; alcohol preferring rats; base; brain tissue; case control; cingulate cortex; density; dorsal raphe nucleus; excitatory neuron; executive function; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; immunocytochemistry; in vivo; indexing; inhibitor/antagonist; inhibitory neuron; mRNA Expression; meetings; morphometry; neuron loss; neuropathology; neurotoxicity; neurotransmission; non-alcoholic; novel diagnostics; problem drinker; psychologic; receptor; receptor binding; research study; response; reuptake; serotonin transporter; uptake

DESCRIPTION (provided by applicant): Alcoholism is one of the most costly drug use problems in the United States and can result in psychiatric and medical diseases and even ultimately in death. Serotonin deficiency in alcoholics is hypothesized based on reduced serotonin metabolites in the cerebrospinal fluid, the efficacy of serotonin agonists and uptake inhibitors in reducing alcohol consumption, biochemical abnormalities in alcohol preferring rat strains and direct observations in human brain, postmortem and in vivo. During the present funding period, we have made findings in alcoholics of changes in serotonin neurons in the dorsal raphe nucleus (DRN) of increased tryptophan hydroxylase (TPH) serotonin-synthesizing enzyme, a decrease in the amount of serotonin transporter and 5-HT1A inhibitory autoreceptor binding and in the prefrontal cortex (PFC) of reduced 5-HT2A receptor binding in alcoholics and in cases with a family history of alcoholism and a decrease in the density of cortical neurons with duration of alcoholism. Changes observed in the DRN related to the duration of alcoholism are consistent with compensatory upregulation; whereas the alterations dependent on family history suggest a biological predisposition to alcoholism. Follow up studies of the serotonin system are proposed to examine these serotonin alterations in more detail and at the cellular level. The brain of 20 subjects meeting DSM-IV criteria for alcohol abuse or dependence and 20 nonpsychiatric controls will be examined. Alcohol abuse/dependence will be diagnosed by psychological autopsy. Aim 1 seeks to define the capacity of DRN neurons to upregulate their function in alcoholics. Computer-assisted stereology of DRN neurons in alcoholics and non-psychiatric controls will determine the total number of DRN neurons and will be compared to the number of DRN neurons that are serotonin synthesizing to determine whether non-serotonergic neurons can change their phenotype to serotonergic in alcoholics. To determine whether the increase in the amount of TPH is due to increase TPH2 gene expression we will perform in situ hybridization. Preliminary studies found a decrease in serotonin transporter (SERT) in alcoholics suggesting the amount of DRN SERT could be a predisposing factor to the reinforcing effects of alcohol. Studies are proposed to examine the amount of SERT mRNA in the DRN to examine molecular responses at a cellular level. Aim 2 examines target neurons in the prefrontal cortex and anterior cingulate cortex. Studies will be performed to determine the density and morphology of protective brain-derived neurotrophic (BDNF) factor neurons and the amount of BDNF mRNA by in situ hybridization. Change in the relative number of GABAergic inhibitory neurons will be determined in adjacent sections. Immunocytochemistry and quantitative morphology will be performed to NeuN and GAD65/67 as markers. The data gathered will suggest mechanisms involved in the pathogenesis of alcoholism. The demonstration of serotonergic neuropathology in the brain of alcoholics may suggest possible pharmacologic therapeutics and new diagnostic approaches using functional brain imaging. PUBLIC HEALTH RELEVANCE Alcoholism is one of the most costly drug use problems in the United States. Alcohol consumption caused by alcoholism can result in psychiatric illness, medical diseases and even ultimately in death. Experiments are proposed in alcoholic and normal control postmortem brain tissues defining how serotonin, a neurotransmitter involved in mood and behavior, is affected by alcoholism and how serotonin deficits can contribute to the onset and maintenance of alcoholism.

描述（由申请人提供）：酗酒是美国最昂贵的药物使用问题之一，可导致精神和医学疾病，甚至最终死亡。基于脑脊液中5-羟色胺代谢物的减少、5-羟色胺激动剂和摄取抑制剂在减少酒精消耗方面的功效、酒精偏好大鼠品系的生化异常以及在人脑、死后和体内的直接观察，推测酗酒者中5-羟色胺缺乏。在目前的资助期间，我们在酗酒者中发现了中缝背核（DRN）中色氨酸羟化酶（TPH）增加的5-羟色胺神经元的变化，5-羟色胺转运体和5-HT 1A抑制性自身受体结合量的减少以及前额叶皮质（PFC）中5-羟色胺转运体和5-HT 1A抑制性自身受体结合量的减少，酗酒者和有酗酒家族史的病例中的HT 2A受体结合以及皮质神经元密度随酗酒持续时间的减少在DRN中观察到的变化与酒精中毒的持续时间是一致的补偿上调，而依赖于家族史的改变表明酒精中毒的生物易感性。建议对5-羟色胺系统进行后续研究，以更详细地在细胞水平上检查这些5-羟色胺的变化。将检查20名符合DSM-IV酒精滥用或依赖标准的受试者和20名非精神病对照者的大脑。酒精滥用/依赖将通过心理尸检进行诊断。目的1旨在确定DRN神经元的能力，以上调其功能的酗酒者。酗酒者和非精神病对照中DRN神经元的计算机辅助体视学将确定DRN神经元的总数，并将其与正在合成5-羟色胺的DRN神经元的数量进行比较，以确定酗酒者中非多巴胺能神经元是否可以将其表型改变为多巴胺能神经元。为了确定TPH量的增加是否是由于TPH 2基因表达的增加，我们将进行原位杂交。初步研究发现，酗酒者的血清素转运体（SERT）减少，这表明DRN SERT的数量可能是酒精强化效应的诱发因素。建议研究检查DRN中SERT mRNA的量，以检查细胞水平上的分子反应。目的2检测前额叶皮层和前扣带皮层的靶神经元。将进行研究以确定保护性脑源性神经营养（BDNF）因子神经元的密度和形态以及通过原位杂交确定BDNF mRNA的量。将在相邻切片中测定GABA能抑制性神经元相对数量的变化。将对NeuN和GAD 65/67作为标志物进行免疫细胞化学和定量形态学检查。收集的数据将提示酒精中毒发病机制。酗酒者大脑中的多巴胺能神经病理学的证明可能表明可能的药物治疗和新的诊断方法，使用功能性脑成像。 公共卫生相关性酗酒是美国最昂贵的药物使用问题之一。酒精中毒引起的酒精消费可能导致精神疾病，医学疾病，甚至最终死亡。在酒精和正常对照死后脑组织中提出实验，以确定参与情绪和行为的神经递质5-羟色胺如何受到酒精中毒的影响，以及5-羟色胺缺乏如何有助于酒精中毒的发生和维持。