PET IMAGING OF THE 5HT TRANSPORTER IN ALCOHOLISM

酗酒时 5HT 转运蛋白的 PET 成像

• 批准号: 2747613
• 负责人: ZSOLT SZABO
• 金额: $ 40.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2747613
• 关键词: affinity labeling; alcoholism /alcohol abuse; bioimaging /biomedical imaging; blood chemistry; clinical research; cortisol; family genetics; fluoxetine; functional ability; genetic polymorphism; hormone regulation /control mechanism; human subject; isoquinolines; magnetic resonance imaging; mental disorder diagnosis; neural transmission; neuroendocrine system; polymerase chain reaction; positron emission tomography; prolactin; radioimmunoassay; radiotracer; serotonin transporter

Impaired serotonin (5-HT) function has been implicated as a possible factor in the biological vulnerability for alcoholism, but most studies of the 5-HT system have been performed in animals or, if performed in humans, they involved only indirect measurements to assess the 5-HT system in the brain. The status of the 5-HT neurons in the brain of living alcohol dependent individuals remains unknown. To investigate the 5-HT system of the brain, quantitative PET studies of the brain 5-HT transporter (5-HTT; an established marker of serotonin neuron integrity) are proposed using [11C]McN5652 as radioligand for four groups of human subjects: family history negative (FHN) controls, family history positive (FHP) controls, FHN recovering alcoholics, and FHP recovering alcoholics. The hypothesis to be tested is that radioligand binding to the 5-HT transporter is significantly reduced as a function of both alcoholism and family history of alcoholism. Serotonin function will also be measured by quantification of plasma prolactin and cortisol increase in response to fluoxetine. The genetic aspect of 5-HT impairment will be investigated by measuring the frequency of specific polymorphisms of the 5-HTT gene. The hypothesis is that FHP alcoholics and FHP controls will have a higher frequency of the s-variant allele, the allele which has been associated with reduced 5-HTT expression/function in in vitro studies. The frequency of the s- variant allele is predicted to be higher in subjects with reduced 5-HTT densities (as determined by PET) and with reduced hormonal responses to fluoxetine. The results of this project will lead to better understanding of the role of serotonin in the biological vulnerability for alcoholism and may lead to improved approaches to prevent and treat alcoholism.

血清素 (5-HT) 功能受损可能是导致 酒精中毒的生物学脆弱性因素，但大多数研究 5-HT 系统已在动物身上进行过，或者如果在 人类，他们只涉及间接测量来评估 5-HT 大脑中的系统。 大脑中5-HT神经元的状态 活着的酒精依赖者仍然未知。 调查 大脑 5-HT 系统，大脑 5-HT 定量 PET 研究 转运蛋白（5-HTT；血清素神经元完整性的既定标志物） 建议使用 [11C]McN5652 作为四组人类的放射性配体 受试者：家族史阴性 (FHN) 对照、家族史 阳性 (FHP) 对照、FHN 戒酒者和 FHP 戒酒者 酗酒者。 要测试的假设是放射性配体结合 5-HT 转运蛋白显着减少，作为两者的函数 酗酒和酗酒家族史。 血清素功能也将通过血浆定量来测量 氟西汀的反应导致催乳素和皮质醇增加。遗传性 5-HT损伤的方面将通过测量 5-HTT 基因特定多态性的频率。 假设 是 FHP 酗酒者和 FHP 对照者的出现频率更高 s 变体等位基因，与减少相关的等位基因 体外研究中的 5-HTT 表达/功能。 s 的频率 预计 5-HTT 降低的受试者中变异等位基因较高 密度（由 PET 测定）和激素反应减少 氟西汀。 该项目的结果将有助于更好地了解 血清素在酒精中毒的生物脆弱性中的作用，并可能 导致改进预防和治疗酗酒的方法。