Arnsten Amy F T, Girgis Ragy R, Gray David L, Mailman Richard B
Department of Neurobiology, Yale Medical School, New Haven, Conmnecticut.
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
Biol Psychiatry. 2017 Jan 1;81(1):67-77. doi: 10.1016/j.biopsych.2015.12.028. Epub 2016 Jan 18.
Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D receptors (DR). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from DR stimulation. DR are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D agonists, e.g., the first full D agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D agonists with better pharmacokinetics, functionally selective D ligands, and DR positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of DR stimulation in the dlPFC that can be translated into clinical practice.
精神分裂症的特征是存在严重的认知缺陷，而目前可用的药物无法缓解这些缺陷。其中许多认知缺陷涉及新进化的背外侧前额叶皮质（dlPFC）功能障碍。精神分裂症患者的大脑显示出dlPFC锥体细胞树突萎缩的证据，可能存在皮质多巴胺减少以及多巴胺D受体（DR）的可能变化。几十年来人们已经认识到，最佳水平的多巴胺对于dlPFC工作记忆功能至关重要，DR刺激会产生许多有益作用。DR集中在灵长类动物dlPFC的树突棘上，在工作记忆任务期间，其刺激会对dlPFC神经元放电和认知表现产生倒U型剂量反应。学术界和制药行业的研究都促使了选择性D激动剂的开发，例如首个完全D激动剂二氢麦角隐亭，低剂量时它可改善猴子的工作记忆。二氢麦角隐亭已开始在精神分裂症或分裂型障碍患者中进行测试。初步结果令人鼓舞，但研究受到该药物药代动力学的限制。然而，这些数据促使人们努力发现和开发改良或新型化合物，包括具有更好药代动力学的D激动剂、功能选择性D配体以及DR正变构调节剂。这些方法中的一种或几种应能优化DR刺激在dlPFC中的有益作用，并将其转化为临床实践。
