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: 7918776
• 负责人: MARK D UNDERWOOD
• 金额: $ 42.38万
• 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/7918776
• 关键词: Activities of Daily Living; Affect; Alcohol abuse; Alcohol consumption; 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 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; Pathogenesis; Phenotype; Predisposing Factor; Predisposition; Prefrontal Cortex; Preventive; Process; Proteins; 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; 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; public health relevance; 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(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。5-羟色胺缺乏症的假说是基于脑脊液中5-羟色胺代谢产物的减少、5-羟色胺激动剂和摄取抑制剂在减少酒精消耗方面的有效性、偏爱酒精的大鼠品系的生化异常以及对人脑、死后和活体的直接观察。在目前的资助期间，我们在酗酒者和有酗酒家族史的病例中发现，酗酒者和有酗酒家族史的病例中，中缝背核(DRN)的5-羟色胺神经元(DRN)的色氨酸羟基酶(TPH)合成酶增加，5-羟色胺转运体和5-HT1A抑制性自身受体结合量减少，前额叶皮质(PFC)5-HT2A受体结合量减少，皮质神经元密度随酒精中毒时间的延长而减少。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是一致的；而依赖于家族病史的变化表明对酒精中毒的生物学易感性。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。20名符合DSM-IV酒精滥用或依赖标准的受试者和20名非精神病对照组的大脑将被检查。酒精滥用/依赖将通过心理尸检来诊断。目的1试图确定酒精患者DRN神经元上调其功能的能力。对酗酒者和非精神病对照组的DRN神经元的计算机辅助体视学将确定DRN神经元的总数，并将其与合成5-羟色胺的DRN神经元的数量进行比较，以确定非5-羟色胺能神经元是否可以将其表型转变为5-羟色胺能神经元。为了确定TPH数量的增加是否由于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5-羟色胺转运体(SERT)减少，提示DRN-SERT的数量可能是酒精强化作用的一个易感因素。研究建议检测DRN中SERT mRNA的数量，以在细胞水平上检测分子反应。目的2观察前额叶皮质和前扣带回皮质的靶神经元。研究将通过原位杂交来确定保护性脑源性神经营养因子(BDNF)因子神经元的密度和形态以及BDNF mRNA的量。GABA能抑制神经元的相对数量的变化将在相邻的切片上确定。以NeuN和GAD65/67为标记物，进行免疫细胞化学和定量形态观察。收集的数据将提示酒精中毒的发病机制。酗酒者脑内5-羟色胺能神经病理的显示可能提示可能的药物疗法和使用脑功能成像的新的诊断方法。与公共健康相关的酒精中毒是美国代价最高的药物使用问题之一。酒精中毒导致的酒精消费会导致精神疾病、内科疾病，甚至最终导致死亡。有人提议在酗酒者和正常对照的死后脑组织中进行实验，以确定5-羟色胺--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5-羟色胺缺乏如何有助于酒精中毒的发生和维持。