CYP2D6, brain structure, and cognitive function in methamphetamine dependence

描述（由申请人提供）：甲基苯丙胺（Meth）依赖者在认知测试中的表现往往比健康的对照个体差。然而，并不是所有的甲基苯丙胺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，但其他人对不滥用药物的健康人表现出焦虑。甲基苯丙胺依赖个体认知功能变异的一个可能来源可能在于甲基苯丙胺使用导致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，基因上易受甲基苯丙胺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脆弱的人差。一个可能的基因候选人，可能适度的神经毒性甲基滥用是基因编码的酶细胞色素P450，家族2，亚家族D，多肽6（CYP 2D 6）。CYP 2D 6是通过羟基化和去甲基化催化甲氧西林代谢的主要酶。在一项有希望的初步研究中，Cherner及其同事（2010）发现，基于CYP 2D 6基因型的Meth强代谢者的Meth依赖参与者在几项认知测试中的表现明显不如中间或弱代谢者。作者推断，由于快代谢者的认知能力最差，因此来自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有关（例如，4-羟甲基苯丙胺），而不是母体化合物本身。然而，这项研究没有测量任何其他神经毒性相关因素。为了解决这一差距在文献中，我们建议测量脑结构的甲基依赖个体谁拥有不同的功能变体的CYP 2D 6基因，使用结构MRI。假设CYP 2D 6快代谢者比中代谢者或慢代谢者经历更多的神经毒性，我们假设快代谢者比中代谢者/慢代谢者更可能表现出理论上反映甲基神经毒性的脑异常，包括灰质体积不足和纹状体结构增大，以及白质纤维组织估计值较低。此外，我们将进行一系列认知测试，并尝试复制Cherner et al.（2010）的发现。我们目前有一个样本的甲基依赖参与者与CYP 2D 6基因型（快速代谢者N = 30;中间/弱代谢者N = 21;和6个受试者尚未基因分型）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CYP 2D 6的功能变体是否会影响大脑结构和认知能力。这项研究的成功完成将确定一个认知功能障碍和脑异常的甲基依赖的风险因素，以及一个潜在的调解甲基诱导的神经毒性。

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.