COMT val158met genotype alters the effects of methamphetamine dependence on dopamine and dopamine-related executive function: preliminary findings.
COMT val158met genotype alters the effects of methamphetamine dependence on dopamine and dopamine-related executive function: preliminary findings.
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DOI：
10.1016/j.psychres.2020.113269
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发表时间：
2020-10
影响因子：
11.3
通讯作者：
Ellis RJ
中科院分区：
文献类型：
--
作者：
Saloner R;Cherner M;Sundermann EE;Watson CW;Iudicello JE;Letendre SL;Kumar A;Ellis RJ
与瓦尔等位基因相比，COMT Val 158 Met多态性的Met等位基因减缓了前额皮质中多巴胺（DA）的代谢并增加了其生物利用度。健康的甲硫氨酸携带者在执行功能（EF）测试中优于Val携带者，但这种“优势”在甲基苯丙胺（METH）依赖中消失。Met-carriers可能不成比例地容易受到METH相关的DA扰动，但尚不清楚COMT是否调节METH对CSF DA生物标志物的影响。参与者为75名METH+和47名METH-男性，他们接受了神经认知测试、COMT基因分型和腰椎穿刺。测定CSF中DA及其代谢产物高香草酸（HVA）。单独的线性模型回归DA，HVA，和HVA/DA比COMT，METH和它们的相互作用。Pearson相关分析了DA和EF之间的关系。显著的相互作用表明，在Met/Met中，METH+具有较低的DA和较高的HVA/DA比值，但不具有瓦尔/Met或瓦尔/瓦尔。Met/Met在METH-中表现出最高的DA水平，而在METH+中Met/Met和Val-携带者之间的DA水平相当。在METH-Met/Met中，较高的DA与较好的EF相关，但不能预测整个样本的EF。在METH- Met/Met中DA更高，但在METH+ Met/Met中出现不一致的基因型-表型特征，这与缓慢的DA清除加剧了MET相关的DA失调的观点一致。
The Met allele of the COMT Val158Met polymorphism slows metabolism and increases bioavailability of dopamine (DA) in the prefrontal cortex compared to the Val allele. Healthy Met-carriers outperform Val-carriers on executive function (EF) tests, yet this ‘advantage’ disappears in methamphetamine (METH) dependence. Met-carriers may be disproportionately vulnerable to METH-related perturbations of DA, yet it is unknown whether COMT modulates METH effects on CSF DA biomarkers. Participants were 75 METH+ and 47 METH- men who underwent neurocognitive testing, COMT genotyping, and lumbar puncture. CSF was assayed for DA and its metabolite, homovanillic acid (HVA). Separate linear models regressed DA, HVA, and HVA/DA ratios on COMT, METH and their interaction. Pearson correlations examined associations between DA and EF. Significant interactions indicated that METH+ had lower DA and higher HVA/DA ratios among Met/Met, but not Val/Met or Val/Val. Met/Met exhibited the highest DA levels among METH-, whereas DA levels were comparable between Met/Met and Val-carriers among METH+. Higher DA correlated with better EF in METH- Met/Met, but did not predict EF in the entire sample. DA was expectedly higher in METH- Met/Met, yet a discordant genotype-phenotype profile emerged in METH+ Met/Met, consistent with the notion that slow DA clearance exacerbates METH-associated DA dysregulation.
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DOI：
10.1073/pnas.111134598
发表时间：
2001-06-05
影响因子：
11.1
作者：
Egan, MF;Goldberg, TE;Weinberger, DR
通讯作者：
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影响因子：
5.3
作者：
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影响因子：
6.1
作者：
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影响因子：
7.4
作者：
Felger JC;Miller AH
通讯作者：
Miller AH
影响因子：
10.6
作者：
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通讯作者：
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