Effects of SLC6A4, BDNF and Ecstasy Use on Brain Structure in Young Adults

描述（由申请人提供）：使用摇头丸（主要含有MDMA）仍然是主要的公共卫生问题，特别是在年轻人中。动物实验表明摇头丸是一种选择性血清素神经毒素。然而，使用摇头丸对人类大脑的影响仍未得到充分研究。对认知结果的研究表明，个体差异巨大，尤其是在执行功能方面。在与摇头丸相关的认知后遗症中，这种差异的一个可能原因是基线血清素功能的个体差异，部分是由血清素转运基因（SLC6A4）的多态性引起的，该基因与血清素信号传导和血清素相关疾病有关。例如，SLC6A4启动子区域（5-HTTLPR）的多态性与健康和抑郁成年人的认知功能和大脑结构有关。此外，SLC6A4内含子2 （STin2）内可变数目串联重复序列的多态性与抑郁症成年人的执行功能有关。到目前为止，报告5-HTTLPR基因型对摇头丸使用者神经认知影响的结果是不一致的。这种差异可能部分归因于脑源性神经营养因子（BDNF）基因型对SLC6A4功能后果的调节作用和SLC6A4基因型不足。此外，到目前为止，还没有研究检验SLC6A4和BDNF基因型是否解释了摇头丸对记忆、情绪和执行功能基础区域大脑结构影响的个体差异。因此，我们的主要目的是确定在控制多种药物使用后，摇头丸使用与低血清素信号相关的基因型是否预示着年轻成年摇头丸使用者较差的认知功能和额叶结构异常。为了做到这一点，我们将结合50名摇头丸使用者、50名MJ使用者（将在当前提案中新登记）和50名正常对照者（已在PI: Medina的一项初步成像遗传学研究中登记）的数据。所有三组（N=150）将接受心理和神经心理测试，并收集DNA样本。基于5-HTTLPR基因型（S型和L/L型携带者平衡），每组30名年轻人将接受高分辨率磁共振成像脑部扫描。我们将研究摇头丸使用、SLC6A4和BDNF基因型、认知功能和额叶结构之间的直接和间接关系。因此，目前的建议将更好地理解使用摇头丸的神经认知后果，并将确定SLC6A4和BDNF基因型是否有助于解释反复使用摇头丸的后果中的个体差异。最终，从这项研究中获得的信息将有助于推进基因靶向生物学治疗，旨在改善年轻人的神经认知功能和减少药物使用。在全球范围内，这项研究将有助于建立更大的知识基础，了解血清素相关基因的变异如何解释对许多血清素相关疾病的易感性和后果的个体差异。

DESCRIPTION (provided by applicant): Ecstasy (primarily containing MDMA) use continues to be major public health problem, especially among young adults. Animal studies suggest that ecstasy is a selective serotonin neurotoxin. However, the effects of ecstasy use on the human brain continue to be understudied. Studies examining cognitive consequences suggest vast individual differences, especially in executive functioning. One possible reason for this variability in ecstasy-related cognitive sequelae is individual variation in baseline serotonin functioning, caused in part by polymorphisms in the serotonin transporter gene (SLC6A4), which is associated with serotonin signaling and serotonin-related diseases. For example, a polymorphism in the promoter region of SLC6A4 (5-HTTLPR) has been associated with cognitive function and brain structure in healthy and depressed adults. Additionally, polymorphism in the variable number of tandem repeats within intron 2 (STin2) of SLC6A4 has been associated with executive functioning in depressed adults. Thus far, results reporting the effects of 5-HTTLPR genotype on neurocognition in ecstasy users are inconsistent. This discrepancy may be due, in part, to the moderating effects of brain-derived neurotrophic factor (BDNF) genotype on SLC6A4 functional consequences and insufficient SLC6A4 genotyping.Furthermore, no studies to date have examined whether SLC6A4 and BDNF genotypes explain individual variability in the effects of ecstasy on brain structure in regions underlying memory, mood and executive functioning. Hence, our primary aim is to determine whether ecstasy use, in combination with genotypes associated with low serotonin signaling, predicts poorer cognitive function and frontolimbic structural abnormalities in young adult ecstasy users, after controlling for polydrug use. To do this, we will combine data from 50 ecstasy users, 50 MJ users (to be newly enrolled in the current proposal) and 50 normal controls (who are already enrolled in a pilot imaging genetics study, PI: Medina). All three groups (N=150) will be administered a psychological and neuropsychological battery and DNA samples will be collected. Based on 5-HTTLPR genotype (balanced for S vs. L/L carriers), 30 young adults from each group will undergo a high-resolution magnetic resonance imaging brain scan. The direct and indirect relationships between ecstasy use, SLC6A4 and BDNF genotypes, cognitive functioning, and frontolimbic structures will be examined. Hence, the current proposal will provide a better understanding of the neurocognitive consequences of ecstasy use and will determine whether SLC6A4 and BDNF genotypes help explain individual differences seen in the consequences of repeated ecstasy use. Ultimately, information gained from this study will help advance genetically targeted biologically based treatments aimed at improving neurocognitive functioning and reducing drug use in young adults. More globally, this study will contribute to the larger knowledge base about how variations in serotonin-associated genes may explain individual differences in susceptibility to and consequences of the numerous serotonin-related diseases. PUBLIC HEALTH RELEVANCE: This project will increase our understanding of the links between genetic variations that affect serotonin signaling, ecstasy (MDMA) consumption, and brain function in young adults. The data will be critical for explaining individual differences in susceptibility for ecstasy-induced thinking problems and brain structure abnormalities. This information will help tailor drug prevention and biologically based intervention programs.