IMAGING THE SEROTONIN TRANSPORTER IN ALCOHOLISM WITH PET

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。5-羟色胺(5-羟色胺)功能受损被认为是酒精中毒生物易感性的一个可能因素，但大多数关于5-羟色胺系统的研究都是在动物身上进行的，如果是在人类身上进行的，它们只涉及间接测量来评估大脑中的5-羟色胺系统。酒精依赖者大脑中5-羟色胺神经元的状态尚不清楚。为了研究大脑的5-羟色胺系统，以[11C]McN5652为放射性配基，对四组受试者进行了脑内5-羟色胺转运体(5-HTT)的PET定量研究：家族阴性(FHN)对照组、家族病史阳性(FHP)对照组、FHN戒酒组和FHP戒酒组。需要检验的假设是，与5-羟色胺转运体结合的放射性配基显著减少，这是酗酒和酗酒家族史的共同作用。5-羟色胺功能也将通过定量测定血浆催乳素和皮质醇对氟西汀的反应而增加。5-羟色胺损伤的遗传学方面将通过测量5-HTT基因的特定多态的频率来进行研究。假设FHP酗酒者和FHP对照组将有更高频率的S变异等位基因，该等位基因已在体外研究中与5-HTT表达/功能降低相关。据预测，S变异等位基因的频率在5-HTT密度降低(由正电子发射计算机断层扫描确定)和对氟西汀的激素反应降低的受试者中更高。该项目的结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，并可能导致改进预防和治疗酒精中毒的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 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 alcoho