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: 6453806
• 负责人: RICHARD DE LA GARZA
• 金额: $ 11.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6453806
• 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

至少有五种亚型的DA受体，d1-d5已经被 在鉴定的同时受体的分布和一些功能 D1、D2和D3受体的后遗症是已知的，关于 D4受体的生理或病理作用很少。 越来越多的证据表明这些受体可能参与其中。 在“新奇”行为中，心理刺激效应，注意力 缺乏性多动障碍、帕金森氏病和抑郁症 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 D4受体在恒河猴脑内的分布图及其比较 与已报道的D4信使核糖核酸位点结合，因为已报道的D4基因对 D4受体，D4受体探针[~3H]U-101,958 (1-benzyl-4-[N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine) 是为目前的研究定制的放射自显影是 在三种不同的动物(N=3)中进行一式三份， 冠状切面(20微米)以测量总长度([H]U-101,958，1 NM)和 在存在的情况下测量非特异性结合的特异性结合 氯氮平或L-745,870的数据是从8个 前后冠状面和75个不同的亚核和 皮质面积[~3H]U-101,958结合的区域特异性分布 被检测到的最高密度(&gt；20pmol/g组织当量) 在一些地区发现了U-101,958个结合部位(氯氮平基线) 前额叶皮质的12、14和9高水平的[~3H]U-101,958 在其他前额叶中也观察到了结合部位(&gt；17pmol/g) 大脑皮层、颞下回、下丘、梭形回， 丘脑室旁核钩、丘脑正中隆起 下丘脑、内侧纵束和海马体 尾状核/壳核中的U-101,958个结合位点清楚地显示在下面 在前额叶皮质和其他皮质区域观察到的水平 发现较低水平的[~3H]U-101,958个结合部位(&lt；12 pmol/g) 丘脑、中脑、桥脑、小脑的特定核团 延髓内[~3H]U-101,958结合的不均一性 丘脑、海马体和皮质的亚核似乎反映了 D4多巴胺受体的谨慎定位如下 从本研究中可以得出以下结论：1.大鼠脑内分布 用[~3H]U101,958测得的D4受体对应于 报告了物种的分布；2分布类似于， 但与D4的mRNA分布不一致；3[~3H]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，并且 因此成为研究D4的合适探针 大脑中的受体；4D4多巴胺受体密度梯度 与多巴胺水平或多巴胺转运体梯度不对应 大脑，表明D4受体上的多巴胺水平调节 可能不同于对于d1和d2受体的致密意义 D4受体在前额叶皮质和海马区的定位 在其他大脑区域的广泛分布，允许推测 这些受体如何与特定的神经精神障碍相关 或精神刺激剂产生的影响D4的放射自显影地图 本文报道的受体分布提供了详细的底物 进一步研究非人灵长类动物的D4受体