Genetic Factors in Human MDMA Toxicity: A PET Study

描述（由申请人提供）： 本探索性/开发性提案的目的是使用5-羟色胺（5-HT）受体配体[18 F] setoperone正电子发射断层扫描（PET）检查使用MDMA（Ectomy）对戒断的人类MDMA使用者大脑皮层中5-HT 2A（5-HT 2A）受体的慢性影响，根据可能影响5-HT 2A受体表达的遗传变异进行表征。 MDMA已被全世界数百万人使用，并且在MDMA给药的一些动物模型中对5-羟色胺（5-HT）轴突有毒。5-HT影响情绪、记忆、睡眠-觉醒周期、焦虑、食欲、身体形象、攻击性、自杀倾向和性功能。因此，5-HT功能的改变对个体具有潜在的广泛影响。突触后5-HT 2A受体介导急性MDMA效应，并且5-HT 2A受体的活性是产生MDMA诱导的轴突毒性所必需的。此外，来自其他研究人员的初步证据表明，5-HT 2A受体可能在突触前5-HT信号改变时表现出代偿性变化，这些变化与轴突切断术或其他MDMA对5-HT神经传递的影响有关。因此，该受体在MDMA使用者中的状态对于理解MDMA的作用机制具有重要意义。5-HT 2A受体水平可能受到遗传变异的影响，这些遗传变异可能混淆5-HT 2A配体结合试验的解释。T102 C单核苷酸多态性（SNP）是一种沉默的SNP，与另一种常见的多态性1438 G/A几乎完全连锁不平衡。T102 C与许多临床病症和5-HT 2A表达水平的改变有关。为了控制该SNP对5-HT 2A受体水平的潜在影响，我们将招募T102 C的C/C或T/T等位基因纯合子的MDMA使用者。为了控制影响5-HT 2A表达的各种其他因素，我们将招募年龄在18-25岁的白人女性，她们不使用激素避孕药，也不吸烟。将20名戒除MDMA至少90天的MDMA使用者（通过头发样本分析验证）与20名从未使用过MDMA的对照组（年龄、性别和基因型匹配）进行比较，以比较大脑皮层中的5-HT 2A水平（通过[18 F] setoperone PET测定）。我们假设，禁欲MDMA用户将有增加5-HT 2A受体的表达一致（但不是证据）减少突触前5-HT释放。由于5-HT可能影响脑容量，我们还将使用结构磁共振成像（MRI）和基于体素的形态测量（VBM）检查局部脑容量。探索性分析将检查5-HT 2A受体和5-HT转运蛋白基因型与MDMA暴露程度以及5-HT 2A水平和脑体积结局指标的潜在相互作用。

DESCRIPTION (provided by applicant): The Aims of this exploratory/developmental proposal are to use the serotonin (5-HT) receptor ligand [18F] setoperone positron emission tomography (PET) to examine the chronic effects of MDMA (Ecstasy) use on serotonin 2A (5-HT2A) receptors in cerebral cortex of abstinent human MDMA users characterized according to genetic variations potentially influencing 5-HT2A receptor expression. MDMA has been used by millions of people worldwide and is toxic to serotonin (5-HT) axons in some animal models of MDMA administration. 5-HT influences mood, memory, sleep-wake cycle, anxiety, appetite, body image, aggression, suicidality, and sexual function. Therefore, alterations in 5-HT function have potentially broad consequences for the individual. The post-synaptic 5-HT2A receptor mediates acute MDMA effects and activity at the 5-HT2A receptor is necessary to produce MDMA-induced axonal toxicity. In addition, preliminary evidence from other researchers suggests that the 5-HT2A receptor may show compensatory changes in the face of altered pre-synaptic 5-HT signaling associated with axotomy or other MDMA effects on 5-HT neurotransmission. Therefore, the status of this receptor in MDMA users is of great importance in understanding the mechanisms of MDMA's effects. Levels of the 5-HT2A receptor may be influenced by genetic variations that could confound the interpretation of 5-HT2A ligand binding assays. The T102C single nucleotide polymorphism (SNP) is a silent SNP in near complete linkage disequilibrium with another common polymorphism, 1438G/A. The T102C has been associated with numerous clinical conditions and with altered levels of 5-HT2A expression. To control for the potential effects of this SNP on 5-HT2A receptor levels, we will enroll MDMA users homozygous for the C/C or T/T alleles of the T102C. To control for various additional factors affecting 5-HT2A expression we will enroll Caucasian females ages 18-25 who do not use hormonal contraception and who are non-smokers. 20 MDMA users abstinent from MDMA at least 90 days (as verified by hair sample analysis) will be compared to 20 controls (matched by age, sex, and genotype) that have never used MDMA to compare 5-HT2A levels in cerebral cortex as assayed by [18F] setoperone PET. We hypothesize that abstinent MDMA users will have increased 5-HT2A receptor expression consistent with (but not proof of) reduced pre-synaptic 5-HT release. Because 5-HT may affect brain volume, we will also examine regional brain volume using structural magnetic resonance imaging (MRI) and voxel-based morphometry (VBM). Exploratory analyses will examine for potential interactions of 5-HT2A receptor and 5-HT transporter genotype with the degree of MDMA exposure and outcome measures of 5-HT2A levels and brain volume.