Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats
Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats
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DOI：
10.1007/s00213-004-1918-3
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发表时间：
2004-12-01
影响因子：
3.4
通讯作者：
Jones, DNC
中科院分区：
文献类型：
--
作者：
Gartlon, J;Szekeres, P;Jones, DNC
依据：Neuromedin-U（NmU）是NMU 1 R和NMU 2 R的激动剂。NmU及其受体，特别是NMU 2 R的脑分布表明NmU具有广泛的中心作用。在协议中，集中管理NmU影响摄食行为，能量消耗和垂体输出。NmU的进一步中枢神经系统（CNS）作用值得研究。目的：通过定位NMU 1 R和NMU 2 R mRNA，并测量行为、内分泌、神经化学和c-fos对侧脑室（i. c. v.）新墨西哥大学方法：测定大鼠NmU与人NMU 1 R和NMU 2 R的结合亲和力和功能效力。使用半定量逆转录聚合酶链反应测定大鼠和人体组织中NMU 1 R和NMU 2 R mRNA的表达。在体内研究中，将NmU i. c. v.给予雄性Sprague-Dawley大鼠，并评估梳理、运动活动和前脉冲抑制（PPI）的变化。在进一步的研究中，在NmU（i. c. v.）后20分钟测量血浆内分泌激素、[ DOPAC + HVA]/[多巴胺]和[5-HIAA]/[5-HT]比率以及Fos样免疫反应性（FLI）水平。结果如下：在功能测定中，NmU以相等的亲和力与NMU 1 R（K-I，0.11 +/- 0.02 nM）和NMU 2 R（K-I，0.21 +/- 0.05 nM）结合，并且对NMU 1 R（EC 50，1.25 +/- 0.05 nM）和NMU 2 R（EC 50，1.10 +/- 0.20 nM）具有相等的活性。在大鼠和人体组织的CNS区域中发现最高水平的NMU 2 R mRNA表达。NMU 1 R mRNA的表达仅限于这两个物种的外周，大鼠杏仁核除外。NmU引起梳理和运动活动的显着增加，但不影响PPI。此外，NmU降低血浆催乳素，但不影响皮质酮，促黄体激素或促甲状腺激素的水平。NmU升高了额叶皮质和下丘脑中5-HT的水平，降低了海马和下丘脑中5-HT代谢产物的水平，但不影响多巴胺的功能。NmU可显著增加杏仁核、额叶皮质和中央杏仁核的FLI。结论：这些数据为NmU及其受体在脑中的广泛作用提供了进一步的证据。
Rationale: Neuromedin-U (NmU) is an agonist at NMU1R and NMU2R. The brain distribution of NmU and its receptors, in particular NMU2R, suggests widespread central roles for NmU. In agreement, centrally administered NmU affects feeding behaviour, energy expenditure and pituitary output. Further central nervous system (CNS) roles for NmU warrant investigation. Objectives: To investigate the CNS role of NmU by mapping NMU1R and NMU2R mRNA and measuring the behavioural, endocrine, neurochemical and c-fos response to intracerebroventricular (i.c.v.) NmU. Methods: Binding affinity and functional potency of rat NmU was determined at human NMU1R and NMU2R. Expression of NMU1R and NMU2R mRNA in rat and human tissue was determined using semi-quantitative reverse-transcription polymerase chain reaction. In in-vivo studies, NmU was administered i.c.v. to male Sprague-Dawley rats, and changes in grooming, motor activity and pre-pulse inhibition (PPI) were assessed. In further studies, plasma endocrine hormones, [ DOPAC + HVA]/[dopamine] and [5-HIAA]/[5-HT] ratios and levels of Fos-like immunoreactivity (FLI) were measured 20 min post-NmU (i.c.v.). Results: NmU bound to NMU1R (K-I, 0.11 +/- 0.02 nM) and NMU2R (K-I, 0.21 +/- 0.05 nM) with equal affinity and was equally active at NMU1R (EC50, 1.25 +/- 0.05 nM) and NMU2R (EC50, 1.10 +/- 0.20 nM) in a functional assay. NMU2R mRNA expression was found at the highest levels in the CNS regions of both rat and human tissues. NMU1R mRNA expression was restricted to the periphery of both species with the exception of the rat amygdala. NmU caused a marked increase in grooming and motor activity but did not affect PPI. Further, NmU decreased plasma prolactin but did not affect levels of corticosterone, luteinising hormone or thyroid stimulating hormone. NmU elevated levels of 5-HT in the frontal cortex and hypothalamus, with decreased levels of its metabolites in the hippocampus and hypothalamus, but did not affect dopamine function. NmU markedly increased FLI in the nucleus accumbens, frontal cortex and central amygdala. Conclusions: These data provide further evidence for widespread roles for NmU and its receptors in the brain.