de Bruin Natasja M W J, Kruse Chris G
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group Translational Medicine & Pharmacology (TMP), c/o Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Curr Pharm Des. 2015;21(26):3739-59. doi: 10.2174/1381612821666150605112105.
5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease.
5-羟色胺6受体（5-HT6R）拮抗剂在动物模型中已显示出对精神分裂症相关多个认知领域的认知障碍具有疗效。在情景记忆、社会认知、执行功能、工作记忆以及其他一些学习和记忆测试的临床前试验中，5-HT6R拮抗剂均有改善作用。相比之下，几乎没有证据表明其对注意力有疗效。进一步研究基于产前暴露于特定环境损伤的神经发育动物模型中的5-HT6R拮抗剂将很有趣，这些模型对与精神分裂症相关的认知障碍具有高度的表面效度、结构效度和预测效度。对5-HT6拮抗剂与抗精神病药物进行更多的附加临床前研究也很重要。已经描述了改善认知的可能作用机制。5-HT6R拮抗剂减少γ-氨基丁酸（GABA）释放和GABA能中间神经元兴奋性，随后解除对谷氨酸和/或乙酰胆碱释放的抑制，从而增强突触可塑性。此外，5-HT6R拮抗剂可改善认知，因为这些化合物增加齿状回中神经细胞黏附分子多唾液酸（NCAM PSA）免疫反应性神经元的数量，抑制哺乳动物雷帕霉素靶蛋白（mTOR）和Fyn酪氨酸激酶，并与多巴胺和3',5'-环磷酸腺苷调节磷酸蛋白-32（DARPP-32）相互作用。有趣的是，越来越多的临床前证据表明，5-HT6R配体对精神分裂症的共病状况如药物滥用、抑郁、焦虑、肥胖和抗精神病药物引起的锥体外系反应可能有额外益处。最后，我们简要概述了目前正在临床开发中用于治疗精神分裂症和阿尔茨海默病认知障碍的5-HT6R化合物。
