LABEL D4 DOPAMINE RECEPTOR IN PREFRONTAL CORTEX & HIPPOCAMPUS OF MONKEY BRAIN

前额皮质中的 D4 多巴胺受体标签

• 批准号: 6116574
• 负责人: RICHARD DE LA GARZA
• 金额: $ 8.72万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116574
• 关键词: animal tissue; behavioral /social science research tag; bioimaging /biomedical imaging; mental disorders; nervous system; pharmacology; psychology; radiography; substance abuse related disorder

At least five subtypes of DA receptors, D1-D5, have been identified While the receptor distribution and some functional sequelae of D1, D2, and D3 receptors are known, information regarding the physiological or pathological role of D4 receptors is scant Mounting evidence indicates potential involvement of these receptors in "novelty-seeking" behaviors, psychostimulant effects, attention deficit hyperactivity disorder, Parkinson's disease and depression To clarify the role of this receptor subtype in primates, we developed a map of D4 receptor distribution in rhesus monkey brain and compared it with reported D4 mRNA sites Because of its reported selectivity for the D4 receptor, the D4 receptor probe [3H]U-101,958 (1-benzyl-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine) was custom-synthesized for the current study Autoradiography was conducted in triplicate in three separate animals (N=3) with adjacent coronal sections (20 um) to measure total ([3 H]U-101, 958, 1 nM) and nonspecific binding Specific binding was measured in the presence of clozapine or L-745,870 Data was generated from eight anterior-to-posterior coronal planes and 75 distinct subnuclei and cortical areas A region-specific distribution of [3H]U-101,958 binding was detected The highest densities (>20 pmol/g tissue equivalents) of [3H]U-101,958 binding sites (clozapine baseline) were found in areas 12, 14 and 9 of the prefrontal cortex High levels of [3H]U-101,958 binding sites (>17 pmol/g) were also observed in other prefrontal cortex regions, inferior temporal gyrus, subiculum, fusiform gyrus, uncus, paraventricular nucleus of thalamus, median eminence of the hypothalamus, medial longitudinal fasciculus, and hippocampus [3H]U-101,958 binding sites in caudate/putamen were clearly below levels observed in the prefrontal cortex and other cortical areas Lower levels (<12 pmol/g) of [3H]U-101,958 binding sites were found in specific nuclei of the thalamus, and the midbrain, pons, cerebellum and medulla The heterogeneity of [3H]U-101,958 binding within subnuclei of the thalamus, hippocampus, and cortex appear to reflect discreet localization of D4 dopamine receptors The following conclusions can be drawn from this study 1 The brain distribution of the D4 receptor, measured with [3H]U101,958, corresponds to the distribution reported for species; 2 The distribution is similar to, but not identical with D4 mRNA distribution; 3 [3H]U-101,958 binding in non-human primate brain appears to reflect D4 receptors, and therefore emerges as a suitable probe for investigation of D4 receptors in the brain; 4 D4 dopamine receptor density gradients do not correspond to dopamine levels or dopamine transporter gradients in brain, suggesting that dopamine level regulation at the D4 receptor may differ than for the D1 and D2 receptor The significance of a dense localization of D4 receptors in prefrontal cortex and hippocampus, and broad distributio n in other brain areas, allows for speculation on how these receptors may relate to specific neuropsychiatric disorders or effects produced by psychostimulants The autoradiographic map of D4 receptor distribution reported herein provides a detailed substrate for further investigation of the D4 receptor in nonhuman primates

至少有五种DA受体亚型，D1-D5，已经被研究。 虽然受体分布和一些功能 D1、D2和D3受体的后遗症是已知的， D4受体的生理学或病理学作用很少 越来越多的证据表明这些受体可能参与 在“寻求新奇”行为、精神刺激效应、注意力 缺陷多动障碍、帕金森病和抑郁症 为了阐明这种受体亚型在灵长类动物中的作用，我们开发了一种 恒河猴脑D4受体分布图及其比较 与报道的D4 mRNA位点，因为其报道的选择性， D4受体，D4受体探针[3 H]U-101，958 （1-苄基-4-[N-（3-异丙氧基-2-吡啶基）-N-甲基]-氨基哌啶） 为当前研究定制合成放射自显影， 在三只单独的动物（N=3）中进行三次重复， 冠状切片（20 μ m）以测量总（[3 H]U-101，958，1 nM）， 非特异性结合特异性结合是在 氯氮平或L-745，870数据来自八个 前后冠状面和75个不同的亚核， [3 H]U-101，958结合的区域特异性分布 最高密度（>20 pmol/g组织当量）的 [3 H]U-101，958结合位点（氯氮平基线）发现于 前额叶皮层12、14和9处[3 H]U-101，958高水平 结合位点（>17 pmol/g）也观察到在其他前额叶 皮质区，颞下回，下托，梭状回， 钩，丘脑室旁核，正中隆起 下丘脑、内侧纵束和海马 尾状核/壳核中的[3 H]U-101，958结合位点明显低于 在前额皮质和其他皮质区域观察到的水平 在小鼠中发现较低水平（<12 pmol/g）的[3 H]U-101，958结合位点， 丘脑、中脑、脑桥、小脑的特定核团 和骨髓内[3 H]U-101，958结合的异质性 丘脑、海马和皮质的亚核似乎反映了 D4多巴胺受体的精确定位 结论：1.脑内分布 用[3 H]U101，958测量的D4受体对应于 报告的物种分布; 2分布与， 但与D4 mRNA分布不一致; 3 [3 H]U-101，958结合 在非人类灵长类动物的大脑中似乎反映了D4受体， 因此成为研究D4的合适探针 多巴胺受体密度梯度（D4 receptor density gradient） 与多巴胺水平或多巴胺转运蛋白梯度不一致， 这表明D4受体的多巴胺水平调节 可能不同于D1和D2受体。 D4受体在前额叶皮层和海马中的定位，以及 广泛分布在其他大脑区域，允许推测 这些受体如何与特定的神经精神疾病相关 D4的放射自显影图 本文报道的受体分布提供了详细的底物 进一步研究非人类灵长类动物的D4受体