Madras Bertha K
Department of Psychiatry, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772-9102, USA.
J Hist Neurosci. 2013;22(1):62-78. doi: 10.1080/0964704X.2012.678199.
The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.
西曼等人于1975年发表在美国国家科学院院刊上的论文，报道了在大脑中发现抗精神病药物受体，这是转化医学研究的一个经典例子。在寻找精神病的病理生理机制时，该团队试图确定与抗精神病药物氟哌啶醇结合的位点。他们的标准是氟哌啶醇以每升一到两纳摩尔的浓度与该位点结合，这与接受治疗的患者脑脊液或血浆水中的氟哌啶醇浓度相当。他们要求重新合成氚标记的氟哌啶醇，并且它很容易检测到脑纹状体中的特异性氟哌啶醇结合位点。由于多巴胺比其他神经递质更有效地结合氟哌啶醇标记的位点，这些位点被命名为抗精神病/多巴胺受体（现称为多巴胺D2受体）。最重要的是，他们发现所有抗精神病药物都以与精神分裂症患者平均每日服用的抗精神病药物剂量直接相关的浓度和效价顺序结合这些位点。他们的发现使得能够筛选新的抗精神病药物，开始在活体患者大脑中测量D2受体，并确定抗精神病药物产生疗效所需的D2受体最低占有率（65%）。这项集体工作通常被视为为精神分裂症的多巴胺假说提供了一个基本基础。
