Department of Neurology, Wake Forest Medical School and Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
J Neurotrauma. 2021 Jan 15;38(2):225-234. doi: 10.1089/neu.2020.7087. Epub 2020 Aug 10.
Dopamine D1 and D2 receptors differ with respect to patterns of regional brain distribution and behavioral effects. Pre-clinical work suggests that D1 agonists enhance working memory, but the absence of selective D1 agonists has constrained using this approach in humans. This study examines working memory performance in mild traumatic brain injury (mTBI) patients when given pergolide, a mixed D1/D2 agonist, compared with bromocriptine, a selective D2 agonist. Fifteen individuals were studied 1 month after mTBI and compared with 17 healthy controls. At separate visits, participants were administered 1.25 mg bromocriptine or 0.05 mg pergolide prior to functional magnetic resonance imaging (MRI) using a working memory task (visual-verbal n-back). Results indicated a significant group-by-drug interaction for mean performance across n-back task conditions, where the mTBI group showed better performance on pergolide relative to bromocriptine, whereas controls showed the opposite pattern. There was also a significant effect of diagnosis, where mTBI patients performed worse than controls, particularly while on bromocriptine, as shown in our prior work. Functional MRI activation during the most challenging task condition (3-back > 0-back contrast) showed a significant group-by-drug interaction, with the mTBI group showing increased activation relative to controls in working memory circuitry while on pergolide, including in the left inferior frontal gyrus. Across participants there was a positive correlation between change in activation in this region and change in performance between drug conditions. Results suggest that activation of the D1 receptor may improve working memory performance after mTBI. This has implications for the development of pharmacological strategies to treat cognitive deficits after mTBI.
多巴胺 D1 和 D2 受体在脑区分布模式和行为效应上存在差异。临床前研究表明，D1 激动剂可增强工作记忆，但缺乏选择性 D1 激动剂限制了其在人类中的应用。本研究考察了轻度创伤性脑损伤（mTBI）患者在使用混合 D1/D2 激动剂培高利特和选择性 D2 激动剂溴隐亭后的工作记忆表现。15 名患者在 mTBI 后 1 个月接受研究，并与 17 名健康对照进行比较。在不同的访问中，参与者在功能磁共振成像（fMRI）前分别服用 1.25mg 溴隐亭或 0.05mg 培高利特，使用工作记忆任务（视觉-言语 n-回）。结果表明，在 n-回任务条件下，平均表现的组-药交互作用显著，mTBI 组在培高利特上的表现优于溴隐亭，而对照组则相反。诊断也有显著影响，mTBI 患者的表现比对照组差，尤其是在服用溴隐亭时，这与我们之前的研究一致。在最具挑战性的任务条件（3 回>0 回对比）下的功能 MRI 激活显示出显著的组-药交互作用，与对照组相比，mTBI 组在培高利特作用下工作记忆回路的激活增加，包括左额下回。在所有参与者中，该区域激活的变化与药物条件之间的表现变化呈正相关。结果表明，D1 受体的激活可能改善 mTBI 后的工作记忆表现。这对开发治疗 mTBI 后认知缺陷的药物策略具有重要意义。
