CHRONIC ETOH--PATHOBEHAVIORAL LESIONS/ THIAMINE STATUS

慢性乙醇--病理行为病变/硫胺素状态

• 批准号: 2047128
• 负责人: Philip Joseph Langlais
• 金额: $ 18.29万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2047128
• 关键词: alcoholic beverage consumption; behavior test; blood tests; choline acetyltransferase; cognition disorders; dementia; ethanol; frontal lobe /cortex; hippocampus; histopathology; laboratory rat; limbic system; necrosis; nutrient drug interaction; nutrition related tag; oxoglutarate dehydrogenase; parietal lobe /cortex; pyruvate dehydrogenase; reversal learning; short term memory; startle reaction; synapses; thiamine deficiency; transaldolase /transketolase

Alcohol abuse is associated with a wide range of cognitive and memory impairments and structural brain changes. The most severe and best recognized types of alcohol-related damage are alcoholic dementia and Wernicke-Korsakoff syndrome. Alcoholism is reportedly diagnosed as the etiologic factor in 7% of all demented patients and alcoholics represent approximately 20% of the admissions to state mental hospitals. Despite the significance of alcohol-related dementias, the etiological roles of alcohol, thiamine deficiency and their interactions remain unclear. Studies of animal models have revealed that long-term exposure of rats to alcohol causes irreversible learning and memory deficits, as well as pathophysiological changes in hippocampal and neocortical cholinergic systems. Other studies have failed to demonstrate behavioral or pathological changes. No studies so far have assessed regional brain thiamine status following prolonged chronic alcohol exposure. Thiamine deficiency alone in humans and animals produces pathologic lesions to thalamus, mammillary bodies, and possibly the neocortex. Recent studies demonstrate that long-term administration of alcohol both impairs intestinal absorption of thiamine and inhibits brain pyrophosphokinase activity necessary for synthesis of the active form of thiamine. The primary goal of the proposed study is to test our hypothesis that neocortical and hippocampal damage is the result of alcohol-induced thiamine deficiency in these structures and related subcortical projection areas. These data will then be used to direct and design more extensive studies of the pathophysiological mechanisms underlying biochemical and pathological changes. The following specific studies will be conducted in rats administered chronic alcohol (32 weeks 20% ETOH in the drinking water) and fed either a thiamine fortified diet or subjected to 3 bouts of thiamine deficiency; l) Following withdrawal and recovery, measure preservation, reference and short-term working memory, and habituation; 2) Determine the levels of thiamine, thiamine esters, and thiamine dependent enzymes in frontal, parietal, and cingulate cortex, hippocampus, septum, thalamus, and mammillary body of both behaviorally tested animals and in separate groups sacrificed at end of 3rd bout of thiamine deficiency (7th month); 3) Determine: i) thickness of white matter and frontal and parietal cortex; ii) neuronal density in frontal and parietal cortex and CA 1 & 3 sectors of hippocampus; iii) number of cholinergic neurons in medial septum, vertical limb of the diagonal band, and nucleus basalis and noradrenergic neurons in the locus coeruleus; iv) choline acetyltransferase, muscarinic receptors and synaptophysin binding densities in cortex and hippocampus; and, v) presence of Wernicke-type pathologic changes in thalamus, mammillary bodies, and brainstem; 4) Determine which of the treatment conditions correlate with the behavioral, pathologic and biochemical disturbances.

酒精滥用与广泛的认知和记忆有关 损伤和大脑结构的变化。最严厉最好的 公认的酒精相关损伤类型是酒精性痴呆， 韦尼克-科萨科夫综合征据报道，酗酒被诊断为 7%的痴呆患者和酗酒者的病因， 大约有20%的人被送进了州立精神病院尽管 酒精相关性痴呆的意义， 酒精、硫胺素缺乏症及其相互作用尚不清楚。 对动物模型的研究表明， 酒精会导致不可逆转的学习和记忆缺陷， 海马和新皮质胆碱能神经元的病理生理变化 系统.其他研究未能证明行为或 病理变化到目前为止，还没有研究评估区域大脑 长期慢性酒精暴露后的硫胺素状态。硫胺素 在人类和动物中单独缺乏会产生病理损伤， 丘脑乳头体可能还有新皮层最近的研究 证明长期饮酒既会损害 肠道吸收硫胺素和抑制脑焦磷酸激酶 合成活性形式的硫胺素所必需的活性。 这项研究的主要目的是检验我们的假设， 新皮质和海马损伤是酒精诱导的结果 这些结构和相关皮质下的硫胺素缺乏 投影区域。这些数据将用于指导和设计更多的 广泛的研究的病理生理机制， 生化和病理变化。以下具体研究将 在给予慢性酒精的大鼠中进行（32周，20%ETOH， 饮用水），并喂食硫胺素强化饮食或 至3次硫胺素缺乏症发作; l）在戒断和恢复后， 测量保存、参考和短期工作记忆， 习惯化; 2）测定硫胺素、硫胺素酯和 额叶、顶叶和扣带皮层中的硫胺素依赖酶， 海马、隔、丘脑和乳头体 试验动物和在第3回合结束时处死的单独组中 硫胺素缺乏症（第7个月）; 3）测定：i）白色厚度 （二）额叶皮层和顶叶皮层神经元密度 和顶叶皮层和海马的CA 1和3部分; iii） 内侧隔，斜角带垂直支， 和蓝斑的基底核和去甲肾上腺素能神经元; iv） 胆碱乙酰转移酶、毒蕈碱受体和突触素结合 皮质和海马中的密度;和，v）Wernicke型 丘脑、乳头体和脑干的病理改变; 确定哪些治疗条件与 行为、病理和生化紊乱。