D3 DOPAMINE RECEPTORS--POTENTIAL ANTIPSYCHOTIC TARGET

D3 多巴胺受体——潜在的抗精神病药物靶点

• 批准号: 2675245
• 负责人: BETH LEVANT
• 金额: $ 10.43万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2675245
• 关键词: 6 hydroxydopamine; antipsychotic agents; autoradiography; brain metabolism; cerebellum; dopamine; dopamine agonists; dopamine antagonists; dopamine receptor; drug receptors; experimental brain lesion; gene expression; glucose metabolism; high performance liquid chromatography; in situ hybridization; innervation; laboratory rat; limbic system; microinjections; neuroanatomy; neurochemistry; neuropharmacology; receptor binding; receptor expression; receptor sensitivity

DESCRIPTION (Adapted from applicant's abstract): The D3 dopamine receptor is a novel receptor which has been implicated as a potential therapeutic target in the treatment of schizophrenia.This proposal addresses the issue of whether the D3 receptor mediates any of the therapeutic and/or side-effects of antipsychotic drugs. The hypothesis is that D3 receptors in limbic brain regions may mediate the therapeutic effects of antipsychotic drugs, while cerebellar D3 receptors may mediate certain neurological side-effects. Molecular, biochemical, pharmacological, anatomical, and behavioral approaches will be used to address the specific aims: (1) to determine how D3 receptors are regulated by tonic dopaminergic activity. The effects of unilateral and bilateral 6-OHDA lesions of the major dopamine projections on the density of D3 receptors and mRNA indiscrete brain regions will be examined using receptor autoradiography, receptor binding, and in situ hybridization. (2) to determine how D3 receptors are regulated by dopamine agonists and antagonists using receptor autoradiography, receptor binding, and in situ hybridization. (3) to determine D3 receptor occupation by antipsychotic drugs in vivo using receptor autoradiography. (4) to determine the effects of D3 receptor stimulation or blockade on neuronal activity in specific brain regions by assessment of (a) Fos expression and (b) cerebral glucose utilization. (5) to determine whether cerebellar D3 receptors have dopaminergic innervation and, if so, the source. Autoradiographic methods, measurement of catecholamines by HPLC-EC, and retrograde tracers will be used. (6) to determine whether cerebellar dopamine receptors are present in humans and other mammalian species using receptor autoradiography and in situ hybridization. (7) to determine the behavioral effects of microinjection of dopamine agonists and antagonists into cerebellar lobule 10. These studies will provide significant information regarding the functional role of D3 receptor, its potential involvement in the effects of antipsychotic drugs, and its suitability as a therapeutic target.

描述（改编自申请人的摘要）：D3多巴胺 受体是一种新的受体，它被认为是一种潜在的 治疗精神分裂症的治疗靶点。该建议 解决了D3受体是否介导任何 抗精神病药物的治疗和/或副作用。 的假设 边缘脑区的D3受体可能介导治疗性的 抗精神病药物的作用，而小脑D3受体可能 介导某些神经副作用。 分子生物化学， 药理学、解剖学和行为学方法将用于 解决具体目标：（1）确定D3受体是如何 由紧张性多巴胺能活性调节。 单方面和 双侧6-OHDA病灶上主要的多巴胺投射密度 D3受体和mRNA的离散脑区将检查使用 受体放射自显影、受体结合和原位杂交。 (2)以确定多巴胺激动剂如何调节D3受体， 拮抗剂，使用受体放射自显影，受体结合和原位 杂交方法 (3)确定抗精神病药物对D3受体的占用 使用受体放射自显影术进行体内药物研究。 (4)确定 D3受体刺激或阻断对神经元活动的影响 通过评估（a）Fos表达和（B） 脑葡萄糖利用 (5)以确定小脑D3 受体有多巴胺能神经支配，如果有，来源。 放射自显影方法，通过HPLC-EC测量儿茶酚胺，以及 将使用逆行示踪剂。 (6)以确定小脑是否 多巴胺受体存在于人类和其他哺乳动物中 使用受体放射自显影和原位杂交。 (7)到 确定微量注射多巴胺激动剂的行为效应 和拮抗剂进入小脑小叶10。 这些研究将提供 关于D3受体功能作用的重要信息， 潜在参与抗精神病药物的作用，及其 适合作为治疗靶点。