MULTIPLE DOPAMINE RECEPTORS AND ANTIPSYCHOTIC DRUGS

抗精神病药物被假定为发挥其临床效果 通过直接阻断大脑和脑下垂体的多巴胺受体。它是 现在清楚地知道存在多个亚型的多巴胺受体，D-1和D-2， 对抗精神病药物有不同的亲和力。多巴胺 受体将通过计算机分析的放射性配基在体外进行表征 多巴胺能~3H配体结合技术的研究 多巴胺敏感的腺苷环化酶(刺激性和抑制性) 并通过调节培养的垂体腺细胞释放催乳素。这个 这些系统的生化和药理学特征将 建议每个人可能识别的多巴胺受体的群体。 这将被损害研究、功能研究和反应所证实。 膜环境和受体结构的修饰 特定的试剂。这样的研究将识别潜在的自体受体， 突触前和突触后的多巴胺受体亚型，并详细介绍一些 区分激动剂和拮抗剂受体的分子机制 腺苷环化酶调节的相互作用和转导。 去神经或慢性疾病引起的多巴胺受体活性降低 用抗精神病药物阻断会导致行为过敏症 伴随着受体数量的增加。这种药物引起的增加 多巴胺受体被认为是迟缓的病因 运动障碍。多巴胺受体亚型对失神经损伤的反应 亚型选择性和非选择性抗精神病药物的慢性阻断 将被调查以确定涉及到的分子机制 受体结合增加或调节过程发生变化。其影响 还将调查使用激动剂进行慢性刺激的可能性。多巴胺 受体周转将利用一种新技术进行评估。受体 将进行放射自显影以确定移植物的解剖位置 多巴胺受体亚型及其是否表现出差异性 对上述操纵的反应。 不同脑多巴胺群体的生化特征 受体有望开发出新的多巴胺能类 激动剂和拮抗剂，具有更特异的治疗作用并降低 副作用的发生率。

Antipsychotic drugs are hypothesized to exert their clinical effects through direct blockade of brain and pituitary dopamine receptors. It is now clear that multiple subtypes of dopamine receptors exist, D-1 and D-2, which have differential affinities for antipsychotic drugs. Dopamine receptors will be characterized in vitro by computer-analyzed radioligand binding techniques with dopaminergic 3H-ligands, by studies of dopamine-sensitive adenylate cyclases (both stimulatory and inhibitory), and by regulation of prolactin release from cultured pituicytes. The biochemical and pharmacological characteristics of these systems will suggest which populations of dopamine receptors that each may identify. This will be confirmed by lesion studies, functional studies, and response to modification of membrane environment and receptor structure with specific reagents. Such studies will identify potential autoreceptors, pre- and post- synaptic dopamine receptor subtypes and detail some of the molecular mechanisms which differentiate agonist from antagonist receptor interaction and transduction to adenylate cyclase regulation. Decreased dopamine receptor activity caused by denervation or chronic blockade with antipsychotic drugs results in behavioral supersensitivity accompanied by an increase in receptor number. Such drug-induced increases in dopamine receptors have been hypothesized to be etiologic in tardive dyskinesia. The response of dopamine receptor subtypes to denervation or chronic blockade with subtype-selective and nonselective antipsychotics will be investigated to determine the molecular mechanisms involved in increased receptor binding or changes in regulatory processes. The effects of chronic stimulation with agonists will also be investigated. Dopamine receptor turnover will be evaluated utilizing a novel technique. Receptor autoradiography will be performed to determine the anatomical location of dopamine receptor subtypes and whether they demonstrate differential responses to the above manipulations. The biochemical characterization of distinct populations of brain dopamine receptors holds promise for the development of new classes of dopaminergic agonists and antagonists with more specific therapeutic action and lowered incidence of side-effects.