Meltzer Herbert Y, Li Zhu, Kaneda Yasuhiro, Ichikawa Junji
Department of Psychiatry, Division of Psychopharmacology, Vanderbilt University School of Medicine, Suite 306, 1601 23rd Avenue, Nashville, TN 37212, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1159-72. doi: 10.1016/j.pnpbp.2003.09.010.
Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.
基于5-羟色胺（5-HT）受体的机制被认为在新一代抗精神病药物（APDs）的作用中起着关键作用。新一代抗精神病药物通常被称为非典型抗精神病药物，因为与第一代抗精神病药物（如氟哌啶醇）相比，它们能够以较低的锥体外系副作用（EPS）发生率达到抗精神病效果。具体而言，Meltzer等人[《药理学与实验治疗学杂志》251（1989）238]提出，强效的5-HT2A受体拮抗作用以及较弱的多巴胺（DA）D2受体拮抗作用是氯氮平及其他明显的非典型抗精神病药物区别于第一代典型抗精神病药物的主要药理学特征。这一假说与喹硫平、奥氮平、利培酮和齐拉西酮的非典型特征相符，这些药物是美国和许多其他国家治疗精神分裂症最常用的药物，以及处于不同研发阶段的大量化合物。随后的研究表明，5-HT1A激动作用可能是5-HT2A拮抗作用的重要结果，并且当与较弱的D2拮抗作用相结合时，用5-HT1A激动作用替代5-HT2A拮抗作用也可能产生一种非典型抗精神病药物。阿立哌唑是最近引入的非典型抗精神病药物，也是一种D2受体部分激动剂，其一些非典型特性可能也归因于其较弱的D2拮抗作用、5-HT2A拮抗作用和5-HT1A激动作用的综合效应[《欧洲药理学杂志》441（2002）137]。相比之下，Kapur和Seeman[《美国精神病学杂志》158（2001）360]提出的替代性“快速解离”假说仅适用于氯氮平和喹硫平，与包括奥氮平、利培酮和齐拉西酮在内的大多数非典型抗精神病药物的“缓慢”解离速率不一致。位于皮质和海马谷氨酸能锥体神经元上的5-HT2A和5-HT1A受体、腹侧被盖区和黑质中DA神经元细胞体以及皮质和海马中GABA能中间神经元上的5-HT2A受体，以及中缝核中的5-HT1A受体可能是非典型抗精神病药物的重要作用位点。同时，有证据表明5-HT2C和5-HT6受体对一些当前抗精神病药物的某些效应具有重要的调节作用。因此，5-HT已成为开发有效抗精神病药物的关键靶点，与DA一起，促使人们寻找具有复杂药理学的新型药物，结束了仅寻找单一受体靶点（如D3或D4受体）及其选择性药物的局面。
