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.

说明(由申请人提供)：摇头丸(主要含有MDMA)的使用仍然是主要的公共卫生问题，特别是在年轻人中。动物研究表明，摇头丸是一种选择性的5-羟色胺神经毒素。然而，摇头丸对人脑的影响仍未得到充分研究。对认知后果的研究表明，个体之间存在巨大差异，尤其是在执行功能方面。摇头丸相关认知后遗症出现这种差异的一个可能原因是基线5-羟色胺功能的个体差异，部分原因是5-羟色胺转运体基因(SLC6A4)的多态性，该基因与5-羟色胺信号和5-羟色胺相关疾病有关。例如，SLC6A4启动子区域(5-HTTLPR)的多态性与健康和抑郁症成年人的认知功能和大脑结构有关。此外，SLC6A4基因内含子2(STin2)内可变数目串联重复序列的多态与抑郁症成年人的执行功能有关。到目前为止，报告5-HTTLPR基因对摇头丸使用者神经认知的影响的结果并不一致。这种差异可能部分是由于脑源性神经营养因子(BDNF)基因对SLC6A4功能后果的缓和效应和SLC6A4基因分型的不足。此外，到目前为止，还没有研究检验SLC6A4和BDNF基因是否解释摇头丸对大脑结构影响的个体差异性，这些区域是记忆、情绪和执行功能的潜在区域。因此，我们的主要目的是确定摇头丸的使用，结合与低5-羟色胺信号相关的基因型，是否预测在控制了多药使用后，年轻的成年摇头丸使用者的认知功能较差和额叶边缘结构异常。要做到这一点，我们将结合来自50名摇头丸使用者、50名MJ使用者(将新加入当前计划)和50名正常对照组(他们已经参加了一项试点成像遗传学研究，PI：Medina)的数据。所有三组(N=150)都将接受心理和神经心理学测试，并收集DNA样本。基于5-HTTLPR基因(S与L/L携带者之间的平衡)，每组30名年轻人将接受高分辨率磁共振脑部扫描。本课程将研究摇头丸使用、SLC6A4和BDNF基因型别、认知功能和额叶边缘结构之间的直接和间接关系。因此，目前的提案将更好地了解摇头丸使用的神经认知后果，并将确定SLC6A4和BDNF基因型别是否有助于解释反复使用摇头丸后果的个体差异。最终，从这项研究中获得的信息将有助于推进旨在改善年轻人神经认知功能和减少药物使用的基因靶向生物治疗。从全球范围来看，这项研究将有助于更广泛的知识库，即5-羟色胺相关基因的变异如何解释许多与5-羟色胺相关的疾病的易感性和后果的个体差异。 公共卫生相关性：这个项目将增加我们对影响5-羟色胺信号、摇头丸(MDMA)消费和年轻人大脑功能的基因变异之间的联系的理解。这些数据将是解释摇头丸引发的思维问题和大脑结构异常易感性的个体差异的关键。这些信息将有助于定制药物预防和基于生物的干预计划。