D3 DOPAMINE RECEPTORS--POTENTIAL ANTIPSYCHOTIC TARGET

描述(摘自申请者摘要)：D3多巴胺 受体是一种新的受体，已被认为是一种潜在的 精神分裂症的治疗靶点。本建议 解决的问题是D3受体是否介导任何 抗精神病药物的治疗和/或副作用。假说 边缘脑区的D3受体可能介导了治疗 抗精神病药物的作用，而小脑D3受体可能 调节某些神经副作用。分子，生化， 将使用药理学、解剖学和行为学方法来 解决具体目标：(1)确定D3受体如何 受紧张性多巴胺能活动的调节。单边和单边效应 双侧6-羟基多巴胺病变的主要多巴胺投射密度 D3受体和不连续脑区的信使核糖核酸将用 受体放射自显影、受体结合和原位杂交。 (2)确定D3受体如何受多巴胺激动剂和 受体放射自显影、受体结合和原位拮抗剂 杂交。(3)抗精神病药物对D3受体占有率的测定 体内药物受体放射自显影。(4)确定 刺激或阻断D3受体对大鼠海马神经元活动的影响 通过评估(A)Fos表达和(B)特定脑区 大脑葡萄糖利用率。(5)测定小脑D3 受体有多巴胺能神经支配，如果是这样的话，就是来源。 放射自显影方法，用高效液相色谱-电化学法测定儿茶酚胺 将使用逆行示踪剂。(6)确定小脑是否 多巴胺受体存在于人类和其他哺乳动物物种中。 使用受体放射自显影和原位杂交。(7)至 测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，其 可能参与抗精神病药物的作用，及其 是否适合作为治疗靶点。

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.