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

SLC6A4、BDNF 和摇头丸的使用对年轻人大脑结构的影响

• 批准号: 7761912
• 负责人: Krista Maurine Lisdahl
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761912
• 关键词: Adolescence; Adult; Affect; Affective; Amygdaloid structure; Animals; Behavioral; Brain; Brain scan; Brain-Derived Neurotrophic Factor; Cognitive; Cognitive deficits; Consumption; Control Groups; DNA; Data; Disease; Drug usage; Enrollment; Equilibrium; Genes; Genetic; Genetic Epistasis; Genetic Markers; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genotype; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Individual Differences; Introns; Link; Magnetic Resonance Imaging; Marijuana; Measures; Memory; Minisatellite Repeats; Modeling; Moods; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurotoxins; Outcome; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Predisposition; Prevention; Process; Promoter Regions; Public Health; Relapse; Reporting; Resolution; Risk; Sampling; Serotonin; Signal Transduction; Structure; Thinking; Variant; addiction; base; cognitive function; depressed; ecstasy; executive function; improved; indexing; intervention program; knowledge base; meetings; neuropsychological; psychologic; public health relevance; serotonin transporter; young adult

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.

描述（由申请人提供）：摇头丸（主要包含MDMA）的使用仍然是主要的公共卫生问题，尤其是在年轻人中。动物研究表明，摇头丸是一种选择性的5-羟色胺神经毒素。但是，摇头丸对人脑的影响仍在研究中。研究认知后果的研究表明了巨大的个体差异，尤其是在执行功能方面。这种变异性在与摇摆不定相关的认知后遗症中变异的可能原因之一是基线血清素功能的个体变化，部分是由5-羟色胺转运蛋白基因（SLC6A4）中的多态性引起的，这与5-羟色胺信号传导和相关性疾病有关。例如，在健康和抑郁的成年人中，SLC6A4（5-HTTLPR）启动子区域的多态性与认知功能和大脑结构有关。此外，SLC6A4内含子2（stin2）内的串联重复数量变量的多态性与抑郁成人的执行功能有关。到目前为止，报告5-HTTLPR基因型对摇头丸使用者神经认知的影响的结果不一致。这种差异可能部分是由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以及SLC6A4基因型的不足。Furthermore。迄今为止，尚无研究尚未研究SLC6A4和BDNF GENOTIND的效果是否在eCnfenty of SLC6A4和BDNF GENOTIS上，对eC的效应效果是否效应效应，对效应的效应，对效应的效应效果是否效应，对效应的效应效果，对效应的效果效应，对效应的效应效果，对效应的效应效果，是否效果效应。功能。因此，我们的主要目的是确定摇头丸的使用与低羟色胺信号传导相关的基因型是否可以预测年轻成人狂喜使用者的认知功能和额骨结构异常较差，此后是在控制Polydrug使用后。为此，我们将结合来自50位摇头丸用户，50个MJ用户（新提案中新招募）的数据和50个正常控件（他们已经参与了一项试验成像遗传学研究，PI：MEDINA）。将对所有三个组（n = 150）进行心理学和神经心理电池，并收集DNA样本。基于5-HTTLPR基因型（与S与L/L载流子保持平衡），来自每组的30名年轻人将接受高分辨率的磁共振成像脑扫描。将检查摇头丸使用，SLC6A4和BDNF基因型，认知功能和额骨结构之间的直接和间接关系。因此，当前的建议将更好地理解摇头丸使用的神经认知后果，并确定SLC6A4和BDNF基因型是否有助于解释在重复狂喜使用后果中看到的个体差异。最终，从这项研究中获得的信息将有助于提高基于遗传靶向的基于生物学的治疗，以改善神经认知功能并减少年轻人的药物使用。在全球范围内，这项研究将有助于更大的知识基础，即有关5-羟色胺相关基因的变异如何解释众多5-羟色胺相关疾病的敏感性和后果的个体差异。 公共卫生相关性：该项目将提高我们对影响5-羟色胺信号传导，摇头丸（MDMA）消费量和大脑功能的遗传变异之间联系的理解。数据对于解释摇头丸引起的思维问题和大脑结构异常的易感性的个体差异至关重要。该信息将有助于量身定制预防药物和基于生物学的干预计划。