Genetic Factors in Human MDMA Toxicity: A PET Study

描述(由申请人提供)：这项探索性/开发性提案的目的是使用5-羟色胺(5-HT)受体配体[18F]setperone正电子发射断层扫描(PET)来检测MDMA(摇头丸)使用对戒断人类MDMA使用者大脑皮层5-HT2A(5-HT2A)受体的慢性影响，其特征是潜在影响5-HT2A受体表达的遗传变异。MDMA已被全世界数百万人使用，在某些MDMA给药的动物模型中，MDMA对5-羟色胺(5-HT)轴突有毒性。5-羟色胺影响情绪、记忆、睡眠-觉醒周期、焦虑、食欲、身体形象、攻击性、自杀和性功能。因此，5-羟色胺功能的改变对个体有潜在的广泛影响。突触后5-HT2a受体介导急性MDMA效应，5-HT2a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-HT2A受体可能在突触前信号改变时显示出代偿性变化，这些变化与轴突切断或其他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了解MDMA的作用机制具有重要意义。5-HT2A受体的水平可能受到基因变异的影响，这些变异可能会混淆5-HT2A配体结合分析的解释。T102C单核苷酸多态(SNP)是一种与另一种常见的1438G/A多态处于接近完全连锁不平衡的沉默SNP。T102C与多种临床症状和5-HT2A表达水平的改变有关。为了控制这种SNP对5-HT2A受体水平的潜在影响，我们将招募纯合子的MDMA用户T102C的C/C或T/T等位基因。为了控制影响5-HT2A表达的各种额外因素，我们将招募年龄在18-25岁、不使用激素避孕药和不吸烟的高加索女性。20名戒除MDMA至少90天的MDMA使用者(通过头发样本分析证实)将与从未使用MDMA的20名对照组(年龄、性别和基因相匹配)进行比较，以比较[18F]setperone PET测定的大脑皮层5-HT2A水平。我们假设戒毒的MDMA使用者将增加5-HT2A受体的表达，这与突触前5-羟色胺释放减少一致(但不是证据)。由于5-羟色胺可能会影响脑体积，我们还将使用结构磁共振成像(MRI)和基于体素的形态计量学(VBM)来检测局部脑体积。探索性分析将检查5-HT2A受体和5-羟色胺转运体基因与MDMA暴露程度的潜在交互作用，以及5-HT2A水平和脑体积的结果指标。

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.