Department of Neurology, University of California, San Francisco, CA, United States; Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States.
Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States; Division of Neurology, VA Northern California Health Care System, United States.
Neuroimage. 2021 Nov 15;242:118472. doi: 10.1016/j.neuroimage.2021.118472. Epub 2021 Aug 12.
The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone.
药物增强皮质多巴胺（DA）张力对健康成年人大脑的认知影响具有可变性。根据倒 U 型函数，人们假设药物反应的个体差异与皮质 DA 活性的基线有关。为了更好地理解沿着该曲线的发散起点对 DA 药物反应的影响，研究人员利用了编码儿茶酚-O-甲基转移酶（COMT）的基因中的一个常见多态性（rs4680），该基因导致皮质 DA 的细胞外水平增加（Met 等位基因）或减少（Val 等位基因）。在这里，我们研究了两种不同机制的多巴胺能药物给药后静息皮质灌注变化的程度是否因 COMT 基因型而异，从而跟踪倒 U 模型的预测。使用动脉自旋标记（ASL）和双盲、自身对照设计，在 75 名健康、基因分型的参与者中，在每种药物（COMT 抑制剂托卡朋、DA D2/3 激动剂溴隐亭和安慰剂）给药后各测量一次灌注。COMT 基因型和药物相互作用，使得 COMT Val 纯合子对两种药物均表现出预先灌注增加，而 Met 纯合子则没有。此外，右侧额下回与托卡朋相关的灌注变化与执行功能任务的改变表现相关。对于影响纹状体 DA 系统功能的遗传多态性（rs1800497），没有发现类似的影响。总之，这些结果表明，药物引起的灌注变化的方向和幅度都为皮质 DA 张力增强反应的个体差异提供了有意义的信息。
