MULTIPLE DOPAMINE RECEPTORS AND ANTIPSYCHOTIC DRUGS

抗精神病药物被假设发挥其临床效果 通过直接阻断大脑和垂体多巴胺受体。 是 现在已经清楚，多巴胺受体存在多种亚型，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体在体外表征 多巴胺能3 H-配体的结合技术，通过研究 多巴胺敏感性腺苷酸环化酶（刺激性和抑制性）， 以及通过调节从培养的垂体细胞释放催乳素。 的 这些系统的生物化学和药理学特征将 表明多巴胺受体的群体，每一个可以识别。 这将通过病变研究、功能研究和缓解来证实 涉及膜环境和受体结构的修饰， 特殊试剂 这些研究将确定潜在的自身受体， 突触前和突触后多巴胺受体亚型，并详细介绍了一些 区分受体激动剂和拮抗剂的分子机制 相互作用和转导到腺苷酸环化酶调节。 失神经支配或慢性多巴胺受体活性降低 用抗精神病药物阻断导致行为超敏 伴随着受体数量的增加。 这种药物引起的增加 多巴胺受体的异常被认为是迟发性痴呆的病因 运动障碍多巴胺受体亚型对去神经支配或 亚型选择性和非选择性抗精神病药慢性阻滞 将进行研究，以确定参与的分子机制， 受体结合增加或调节过程发生变化。 的影响 也将研究用激动剂的慢性刺激。 多巴胺 将利用新技术评价受体更新。 受体 将进行放射自显影以确定 多巴胺受体亚型以及它们是否表现出差异 对上述操作的反应。 脑内多巴胺不同种群的生化特征 受体为开发新的多巴胺能神经递质提供了希望。 激动剂和拮抗剂具有更特异的治疗作用， 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 regulator 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.