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对照者差。然而，并不是所有的Meth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。Meth依赖者认知功能变异的一个可能来源可能是Meth的使用对神经毒性的遗传易感性。在其他因素保持不变的情况下，遗传上易受甲基苯丙氨酸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遗传上不脆弱的人更差。一个可能的候选基因是编码细胞色素P450，家族2，亚家族D，多肽6(CYP2D6)的基因，它可能会在Meth滥用中缓和神经毒性。CYP2D6是通过羟基化和去甲基化来催化Meth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基因的Meth广泛代谢者在几项认知测试中的表现明显逊于那些处于中间或较差代谢者的参与者。作者推断，由于广泛的代谢剂的认知表现最差，甲基苯丙胺依赖引起的神经毒性可能优先与甲基苯丙胺的代谢副产物有关，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，我们建议使用结构磁共振技术来测量拥有不同功能变异的CYP2D6基因的Meth依赖者的大脑结构。假设广泛代谢物的神经毒性比中等或低度代谢物更强，我们假设过度代谢物将比中等/低度代谢物更有可能出现脑部异常，这些异常已经被理论上反映了甲基神经毒性，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较低估计。此外，我们将进行一系列认知测试，并试图复制Cherner等人的发现。(2010)。我们目前有一个具有CYP2D6基因(广泛代谢物N=30；中等/差代谢物N=21；6名受试者尚未进行基因分型)和结构性MRI扫描的甲基依赖受试者样本。这项拟议的工作旨在将24名参与者添加到这个数据集，以测试CYP2D6的功能变体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Meth依赖中认知功能障碍和脑异常的风险因素，以及Meth诱导的神经毒性的潜在调节剂。

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.