CYP2D6, brain structure, and cognitive function in methamphetamine dependence

描述（由申请人提供）：依赖甲基苯丙胺（冰毒）的个体在认知测试中的表现往往比健康对照个体差。然而，并非所有冰毒依赖者都表现出认知缺陷；虽然有些人有相当大的认知问题，但其他人的表现与不滥用药物的健康人相当。冰毒依赖个体认知功能变异的一个可能来源可能是对冰毒使用引起的神经毒性发展的遗传易感性。在其他因素保持不变的情况下，在基因上易受冰毒诱导的神经毒性影响的个体，在认知测试中的表现预计会比那些基因上不易受影响的个体更差。一种可能的遗传候选基因可能会减轻甲基安非他明滥用的神经毒性，它是编码细胞色素P450酶，家族2，亚家族D，多肽6 （CYP2D6）的基因。CYP2D6是通过羟基化和去甲基化催化甲基代谢的主要酶。在一项有希望的初步研究中，Cherner及其同事（2010）发现，基于CYP2D6基因型的甲基苯丙胺广泛代谢者的甲基苯丙胺依赖参与者在几项认知测试中的表现明显差于中度或不良代谢者。作者推断，由于广泛代谢者的认知表现最差，甲基苯丙胺依赖的神经毒性可能优先与甲基苯丙胺的代谢副产物（如4-羟甲基苯丙胺）有关，而不是母体化合物本身。然而，这项研究没有测量任何其他与神经毒性相关的因素。为了解决文献中的这一空白，我们建议使用结构MRI测量具有不同CYP2D6基因功能变体的冰毒依赖个体的大脑结构。假设CYP2D6广泛代谢物比中等或较差代谢物具有更大的神经毒性，我们假设广泛代谢物比中等或较差代谢物更有可能表现出反映甲基苯丙胺神经毒性的大脑异常，包括灰质体积缺陷和纹状体结构扩大，以及白质纤维组织的估计较低。此外，我们将进行一系列认知测试，并试图复制Cherner等人（2010）的研究结果。我们目前有一个CYP2D6基因型的冰毒依赖参与者样本（广泛代谢者N = 30；中等/差代谢者N = 21； 6名尚未进行基因分型的受试者）和结构MRI扫描。这项工作的目的是在这个数据集中增加24名参与者，以测试CYP2D6的功能变异是否会影响大脑结构和认知表现。这项研究的成功完成将确定冰毒依赖中认知功能障碍和大脑异常的危险因素，以及冰毒诱导的神经毒性的潜在调节因素。

DESCRIPTION (provided by applicant): Individuals who are methamphetamine (Meth) dependent tend to perform worse on cognitive tests than healthy comparison individuals. However, not all Meth-dependent individuals display cognitive deficits; while some have considerable cognitive problems, others perform comparably to healthy individuals who do not abuse drugs. One possible source of variability in cognitive function in Meth-dependent individuals may lie in the genetic susceptibility to the development of neurotoxicity from Meth use. With other factors held constant, individuals who are genetically vulnerable to Meth-induced neurotoxicity would be expected to perform worse on cognitive tests than those who are not genetically vulnerable. One possible genetic candidate which may moderate neurotoxicity in Meth abuse is the gene which codes for the enzyme Cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6). CYP2D6 is the primary enzyme to catalyze Meth metabolism by hydroxylation and demethylation. In a promising preliminary study, Cherner and colleagues (2010) found that Meth-dependent participants who were extensive metabolizers of Meth based on CYP2D6 genotype performed significantly worse on several cognitive tests than those who were intermediate or poor metabolizers. The authors reasoned that, because extensive metabolizers had the worst cognitive performance, neurotoxicity from Meth dependence may be preferentially related to the metabolic byproducts of Meth (e.g., 4- hydroxymethamphetamine), rather than the parent compound itself. However, this study did not measure any other correlates of neurotoxicity. To address this gap in the literature, we propose to measure the brain structure of Meth-dependent individuals who possess different functional variants of the CYP2D6 gene, using structural MRI. Assuming that CYP2D6 extensive metabolizers experience more neurotoxicity than intermediate or poor metabolizers, we hypothesize that extensive metabolizers will be more likely than intermediate/poor metabolizers to exhibit brain abnormalities which have been theorized to reflect Meth- neurotoxicity, including gray matter volume deficits and enlargement of striatal structures, as well as lower estimates of white-matter fiber organization. In addition, we will administer a battery of cognitive tests and attempt to replicate the findings of Cherner et al. (2010). We presently have a sample of Meth-dependent participants with CYP2D6 genotype (extensive metabolizers N = 30; intermediate/poor metabolizers N = 21; and 6 subjects yet to be genotyped) and structural MRI scans. The proposed work aims to add 24 participants to this dataset to test whether functional variants of CYP2D6 influence brain structure and cognitive performance. Successful completion of this research would identify a risk factor for cognitive dysfunction and brain abnormalities in Meth dependence, as well as a potential moderator of Meth-induced neurotoxicity.