Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience, David Geffen School of Medicine, Los Angeles, California, USA.
Brain Research Institute, UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Addict Biol. 2021 May;26(3):e12950. doi: 10.1111/adb.12950. Epub 2020 Aug 6.
Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (β = -0.254; p = 0.035), but not in control subjects (β = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.
慢性甲基苯丙胺使用与大脑结构异常有关，这可能反映了与药物代谢有关的神经毒性。由于细胞色素 P450 2D6（CYP2D6）酶是甲基苯丙胺代谢的核心，其活性的基因多态性可能会调节甲基苯丙胺对大脑结构和功能的影响。本研究探讨了 CYP2D6 基因型与甲基苯丙胺使用者大脑结构和认知测量之间的关系。基于遗传变异的功能，在 82 名符合《精神障碍诊断与统计手册》第四版（DSM-IV）标准的甲基苯丙胺依赖者（Methamphetamine-dependent，METH）和 79 名健康对照者中确定了 CYP2D6 活性评分，他们完成了认知功能测试（即注意力、记忆和执行功能）；大多数人还接受了结构磁共振成像（Magnetic Resonance Imaging，MRI）评估（METH 组 66 人，对照组 52 人）。CYP2D6 活性评分与全脑皮质厚度之间的关系因组而异（交互作用 p = 0.024），因为 CYP2D6 活性增加与 METH 使用者的皮质厚度变薄有关（β = -0.254；p = 0.035），但在对照组中没有关系（β = 0.095；p = 0.52）。CYP2D6 活性与组之间的相互作用对海马体积没有统计学意义（p > 0.05），但两者的海马都显示出与皮质厚度相似的趋势（METH 使用者呈负相关关系[ps < 0.05]，对照组无相关关系[ps > 0.50]）。METH 使用者的认知评分低于对照组（p = 0.007），但 CYP2D6 活性评分与组之间的认知没有交互作用（p > 0.05）。结果表明，与更高酶活性相关的 CYP2D6 基因型可能使大脑结构对甲基苯丙胺诱导的缺陷具有易感性。这些影响的行为后果尚不清楚，需要进一步研究。
