PET IMAGING OF THE 5HT TRANSPORTER IN ALCOHOLISM

5-羟色胺（5-HT）功能受损可能是 酗酒的生物脆弱性因素，但大多数研究 已经在动物中进行了5-HT系统，或者，如果在 人类，他们只涉及间接测量，以评估5-HT 大脑中的系统。 脑内5-羟色胺神经元的状态 酒精依赖者仍然未知。 探讨 大脑的5-HT系统，大脑5-HT的定量PET研究 转运蛋白（5-HTT;一种确定的5-羟色胺神经元完整性标志物） 建议使用[11 C] McN 5652作为四组人的放射性配体 受试者：家族史阴性（FHN）对照，家族史 阳性（FHP）对照组、FHN恢复期酗酒者和FHP恢复期 酗酒者 待检验的假设是放射性配体与 5-羟色胺转运蛋白作为这两种作用的函数显著降低 酗酒和酗酒家族史。 血清素功能也将通过定量血浆 催乳素和皮质醇对百忧解有反应而增加。遗传 5-HT损伤的方面将通过测量 5-HTT基因特异性多态性的频率。 的假设 FHP酗酒者和FHP控制者将有更高的 S-变异等位基因，与减少的 5-体外研究中的HTT表达/功能。 频率的S- 在5-HTT降低的受试者中，预测变异等位基因较高 密度（由PET确定）和降低的激素反应， 氟西汀。 该项目的成果将有助于更好地了解 5-羟色胺在酒精中毒的生物脆弱性中的作用， 从而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.