Schreiber Rudy, Newman-Tancredi Adrian
Suadeo Drug Discovery Consulting LLC, 8 Linden Street #2, Watertown, 02472 MA, USA; Department of Behavioral Physiology, University of Groningen, Groningen, The Netherlands.
Neurolixis Inc., San Diego, CA, USA.
Neurobiol Learn Mem. 2014 Apr;110:72-80. doi: 10.1016/j.nlm.2013.12.015. Epub 2014 Jan 11.
Atypical antipsychotics fail to substantially improve cognitive impairment associated with schizophrenia (CIAS) and one strategy to improve it is to stimulate adult neurogenesis in hippocampus, because this structure is part of an altered circuitry that underlies aspects of CIAS. Deficits in hippocampal adult neurogenesis may disrupt cognitive processes that are dependent on newborn neurons, such as pattern separation (the formation of distinct representations of similar inputs). Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT(1A) receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus. We hypothesize that use of antipsychotics possessing 5-HT(1A) receptor agonist properties may protect against or attenuate CIAS by a dual mechanism: a favorable influence on adult neurogenesis that develops upon sustained drug treatment, and an increase in dopamine levels in the prefrontal cortex that starts upon acute treatment. This hypothesis is consistent with the beneficial properties of 5-HT(1A) activation reported from pilot clinical studies using 5-HT(1A) agonists as adjunct to antipsychotic treatments. Recent antipsychotics, including clozapine and aripiprazole, exhibit different levels of 5-HT(1A) receptor partial agonism and may, therefore, differentially elicit hippocampal adult neurogenesis and increases in prefrontal cortex dopamine. We suggest that comparative studies should elucidate correlations between effects of antipsychotics on adult neurogenesis and prefrontal cortex dopamine with effects on performance in translational cognitive tasks known to involve new born neurons, such as tasks involving pattern separation, and working memory tasks sensitive to prefrontal cortex dopamine levels.
非典型抗精神病药物不能显著改善精神分裂症相关的认知障碍（CIAS），而改善该障碍的一种策略是刺激海马体中的成年神经发生，因为该结构是CIAS相关神经回路改变的一部分。海马体成年神经发生的缺陷可能会破坏依赖新生神经元的认知过程，如模式分离（对相似输入形成不同表征）。因此，能够增加海马体成年神经发生的机制具有治疗意义，一个有前景的分子靶点是激活5-羟色胺5-HT(1A)受体，因为该位点的激动剂可增加齿状回中的成年神经元增殖。我们假设，使用具有5-HT(1A)受体激动剂特性的抗精神病药物可能通过双重机制预防或减轻CIAS：持续药物治疗对成年神经发生产生有利影响，急性治疗开始时前额叶皮质多巴胺水平升高。这一假设与使用5-HT(1A)激动剂作为抗精神病治疗辅助药物的初步临床研究报告的5-HT(1A)激活的有益特性一致。包括氯氮平和阿立哌唑在内的新型抗精神病药物表现出不同程度的5-HT(1A)受体部分激动作用，因此可能不同程度地引发海马体成年神经发生和前额叶皮质多巴胺增加。我们建议，比较研究应阐明抗精神病药物对成年神经发生和前额叶皮质多巴胺的影响与对已知涉及新生神经元的转化认知任务（如涉及模式分离的任务和对前额叶皮质多巴胺水平敏感的工作记忆任务）表现的影响之间的相关性。
