Lidow Michael S, Koh Phil-Ok, Arnsten Amy F T
Department of Oral and Craniofacial Biological Sciences and Program of Neuroscience, University of Maryland, Baltimore, Maryland 21201, USA.
Synapse. 2003 Feb;47(2):101-8. doi: 10.1002/syn.10143.
Dopamine D1 receptors have critical neuromodulatory influences on the working memory functions of the prefrontal cortex, a brain region affected in many neuropsychiatric disorders. When D1 receptor agents are administered to rats or monkeys performing working memory tasks, an "inverted U" dose/response function is typically observed, whereby either too little or too much D1 receptor stimulation impairs working memory. There are two subtypes of D1 receptors, the D1A and the D1B (also known as the D1 and D5, respectively), but the relative contributions of these subtypes to prefrontal cortical function are not known, as there are no pharmacological agents that can distinguish between these receptors. Thus, genetically altered mice are needed to address this question. However, it is not known whether the mouse prefrontal cortex contains both D1A and D1B receptor subtypes, nor is it known whether mice will exhibit responses to D1 receptor agonists similar to those seen in rats and monkeys. The current study examined these issues by immunostaining the mouse brain with specific antibodies directed at the D1A and D1B receptor subtypes and by assessing the effects of increasing doses of a D1 receptor agonist, SKF81297, on spatial working memory performance in mice. Results indicate that mice are generally similar to monkeys and rats, expressing both D1A and D1B receptors in the prefrontal cortex and exhibiting an inverted "U" dose/response curve when administered SKF81297.
多巴胺D1受体对前额叶皮质的工作记忆功能具有关键的神经调节作用，前额叶皮质是一个在许多神经精神疾病中都会受到影响的脑区。当给执行工作记忆任务的大鼠或猴子施用D1受体药物时，通常会观察到一种“倒U形”剂量/反应函数，即D1受体刺激过少或过多都会损害工作记忆。D1受体有两种亚型，即D1A和D1B（也分别称为D1和D5），但由于没有能够区分这些受体的药物，这些亚型对前额叶皮质功能的相对贡献尚不清楚。因此，需要基因改造的小鼠来解决这个问题。然而，尚不清楚小鼠前额叶皮质是否同时含有D1A和D1B受体亚型，也不清楚小鼠对D1受体激动剂的反应是否与大鼠和猴子相似。本研究通过用针对D1A和D1B受体亚型的特异性抗体对小鼠脑进行免疫染色，以及评估递增剂量的D1受体激动剂SKF81297对小鼠空间工作记忆表现的影响，来研究这些问题。结果表明，小鼠一般与猴子和大鼠相似，在前额叶皮质中同时表达D1A和D1B受体，并且在施用SKF81297时呈现倒“U”形剂量/反应曲线。
