PET IMAGING OF THE 5HT TRANSPORTER IN ALCOHOLISM

5-羟色胺(5-HT)功能受损可能是一种 酒精中毒生物易感性的因素，但大多数研究 已经在动物身上进行了5-羟色胺系统的研究，如果是在 人类，他们只涉及间接测量来评估5-羟色胺 大脑中的系统。5-羟色胺神经元在大鼠脑内的分布 仍然活着的酒精依赖者仍不清楚。去调查 脑内5-羟色胺系统及脑内5-羟色胺的PET定量研究 转运蛋白(5-HTT；5-羟色胺神经元完整性的公认标记物) 建议使用[11C]McN5652作为四组人的放射性配基 研究对象：家族史阴性(FHN)对照、家族史 阳性(FHP)对照、FHN戒酒和FHP康复 酗酒者。需要检验的假设是放射性配基结合到 作为两者的函数，5-羟色胺转运体显著减少 酗酒和酗酒家族史。 5-羟色胺功能也将通过量化血浆来测量 催乳素和皮质醇对氟西汀的反应增加。基因 5-羟色胺损伤的方面将通过测量 5-HTT基因特异性多态频率。假说 FHP酗酒者和FHP控制组将有更高的频率 S变异的等位基因，该等位基因已被认为与减少 5-HTT的体外表达/功能研究。S的频率-- 预测5-HTT降低的受试者的变异等位基因更高 密度(由PET确定)和荷尔蒙反应降低 氟西汀。 该项目的成果将有助于更好地理解 5-羟色胺在酒精中毒生物易感性中的作用 改进预防和治疗酒精中毒的方法。

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.