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: 7525647
• 负责人: MARK D UNDERWOOD
• 金额: $ 41.67万
• 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/7525647
• 关键词: Activities of Daily Living; Affect; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Anterior; Appendix; 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; Count; DSM-IV; Data; Dependence; Development; Diagnosis; Disease; Drug usage; Enzymes; Equilibrium; Family history of; Follow-Up Studies; Funding; Gene Expression; Glutamate Decarboxylase; Glutamates; HTR2A gene; Human; Image Analysis; In Situ Hybridization; Individual; Interneurons; Label; Maintenance; Measures; Medical; Messenger RNA; Methods; Mixed Function Oxygenases; Molecular; Moods; Morphology; Neurons; Neurotransmitters; Numbers; Pathogenesis; Phenotype; Predisposing Factor; Predisposition; Prefrontal Cortex; Preventive; Process; Proteins; Public Health; Rat Strains; Relative (related person); Reporting; Serotonin; Serotonin Agonists; Serotonin Receptor 5-HT1A; Serotonin Receptor 5-HT2A; Silver; Source; Staining method; Stains; System; TDO2 gene; Therapeutic; Tissues; Transcript; Tryptophan; Tryptophan 5-monooxygenase; Tryptophanase; 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; morphometry; neuron loss; neuropathology; neurotoxicity; neurotransmission; non-alcoholic; novel diagnostics; problem drinker; psychologic; 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，甚至最终导致死亡。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减少酒精消耗的功效、嗜酒大鼠品系的生化异常以及在人类大脑、死后和体内的直接观察，对酗酒者的5 -羟色胺缺乏症进行了假设。在目前的资助期内，我们在酗酒者中隔背核（DRN）的5 -羟色胺神经元中发现了色氨酸羟化酶（TPH） 5 -羟色胺合成酶增加的变化。5-羟色胺转运体和5-HT1A抑制性自身受体结合量的减少，以及酗酒者和有酗酒家族史的患者前额叶皮层（PFC） 5-HT2A受体结合减少，以及随着酗酒持续时间的延长，皮质神经元密度降低。在DRN中观察到的与酒精中毒持续时间相关的变化与代偿性上调一致；然而，依赖于家族史的改变表明了酒精中毒的生物学倾向。对血清素系统的后续研究被提议在细胞水平上更详细地检查这些血清素的改变。20名符合DSM-IV酒精滥用或依赖标准的受试者和20名非精神病学对照者的大脑将被检查。酒精滥用/依赖将通过心理解剖来诊断。目的1旨在确定DRN神经元在酗酒者中上调其功能的能力。计算机辅助的酗酒者和非精神病对照的DRN神经元立体学将确定DRN神经元的总数，并将与合成5 -羟色胺的DRN神经元的数量进行比较，以确定酗酒者的非5 -羟色胺能神经元是否能改变其表型为5 -羟色胺能神经元。为了确定TPH量的增加是否由于TPH2基因表达的增加，我们将进行原位杂交。初步研究发现，酗酒者血清素转运体（SERT）降低，这表明DRN SERT的量可能是酒精增强作用的一个易感因素。研究建议检查DRN中SERT mRNA的数量，以检查细胞水平上的分子反应。目的2检查目标神经元在前额皮质和前扣带皮层。研究将通过原位杂交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BDNF mRNA的数量。gaba能抑制神经元相对数量的变化将在相邻切片中确定。将NeuN和GAD65/67作为标记进行免疫细胞化学和定量形态学检测。收集到的数据将提示酒精中毒发病机制。酗酒者大脑中血清素能神经病理学的证明可能提示可能的药物治疗和使用功能脑成像的新诊断方法。酗酒是美国最昂贵的药物使用问题之一。由酒精中毒引起的饮酒会导致精神疾病、医学疾病，甚至最终导致死亡。在酒精中毒和正常对照的死后脑组织中进行实验，以确定血清素（一种参与情绪和行为的神经递质）如何受到酒精中毒的影响，以及血清素缺乏如何导致酒精中毒的发生和维持。