Autoregulation of dopamine release and metabolism by intrastriatal nigral grafts as revealed by intracerebral dialysis.
Autoregulation of dopamine release and metabolism by intrastriatal nigral grafts as revealed by intracerebral dialysis.
复制标题
脑内透析揭示纹状体内黑质移植物对多巴胺释放和代谢的自动调节。
DOI：
10.1016/0306-4522(87)90207-7
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发表时间：
1987
期刊：
影响因子：
3.3
通讯作者：
Björklund,A
中科院分区：
文献类型：
--
作者：
Strecker,RE;Sharp,T;Brundin,P;Zetterström,T;Ungerstedt,U;Björklund,A
使用脑内透析技术在体内检查中脑多巴胺神经元的纹状体内移植物对多巴胺释放和代谢的自动调节。将富含多巴胺的细胞悬浮移植物植入黑质纹状体多巴胺通路单侧 6-羟基多巴胺完全损伤的大鼠尾壳核头部。六个月后的行为测试表明，移植物已经逆转了病变引起的旋转行为。在氟烷麻醉的移植大鼠中，在基础条件下以及低剂量（0.05mg/kg）和高剂量（0.5mg/kg）多巴胺受体激动剂阿扑吗啡后，双侧监测纹状体多巴胺及其代谢物3,4-二羟基苯乙酸和高香草酸的细胞外水平。来自移植纹状体的灌注液显示多巴胺水平与完整对侧纹状体的灌注液没有统计学差异，表明移植物多巴胺的基线释放接近正常。类似地，接枝侧的 3-4-二羟基苯乙酸和高香草酸水平也得到很好的恢复（分别为对照值的 67% 和 52%）。与之前的观察结果一致，从移植侧收集的灌注液中测得的血清素代谢物 5-羟基吲哚乙酸水平显着高于正常水平。随后的组织学分析显示大的移植物富含含多巴胺的神经元（平均值±SEM数量等于3138±630），在探针周围的宿主尾壳核区域中产生大约正常密度的含多巴胺纤维。 0.05 mg/kg（皮下）阿扑吗啡治疗不会影响从移植纹状体中恢复的细胞外多巴胺，而完整侧细胞外 DA 最多减少 30%。然而，随后注射 0.5 mg/kg 阿扑吗啡导致从移植纹状体（最多减少 40%）和完整纹状体（最多减少 80%）中回收的多巴胺大幅减少。低剂量和高剂量的阿扑吗啡都会降低细胞外多巴胺代谢水平，这种反应对于完整侧和移植侧来说基本上是相似的。最后，添加到灌注培养基中的多巴胺再摄取阻滞剂诺米芬辛 (10−5M) 使从移植纹状体和完整纹状体收集的灌注液中的多巴胺产生类似的大幅增加，而 3,4-二羟基苯乙酸和高香草酸没有变化。结果表明，多巴胺受体介导的自动调节控制和多巴胺再摄取通常在黑质纹状体多巴胺途径中起作用，尽管移植神经元释放的多巴胺对阿扑吗啡治疗不太敏感，但也在纹状体内黑质移植物中发挥作用。有人提出，多巴胺自动调节和负反馈是多巴胺移植物功能的强直调节的重要生理机制，并且这可能足以通过纹状体内黑质移植物恢复运动和感觉运动行为。
The autoregulation of dopamine release and metabolism by intrastriatal grafts of mesencephalic dopamine neurons was examinedin vivousing an intracerebral dialysis technique. Dopamine-rich cell suspension grafts were implanted into the head of the caudate putamen in rats with complete unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. Six months later behavioural tests indicated that the grafts had reversed the lesion-induced rotational behaviour. Extracellular levels of striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were monitored bilaterally in the halothane-anaesthetized grafted rat, both under basal conditions, and also following low (0.05mg/kg) and high (0.5mg/kg) doses of the dopamine receptor agonist apomorphine. The perfusate from the grafted striatum showed levels of dopamine which were not statistically different from those of the intact contralateral striatum, indicating that the baseline release of dopamine from the graft was close to normal. Similarly, 3-4-dihydroxyphenylacetic acid and homovanillic acid levels were well recovered on the grafted side (67% and 52%, respectively, of control values). Consistent with previous observations, levels of the serotonin metabolite 5-hydroxyindoleacetic acid measured in perfusate collected from the grafted side was elevated significantly above normal. Subsequent histological analysis revealed large grafts, rich in dopamine-containing neurons (mean± SEMnumber equalled3138 ± 630), giving rise to an approximately normal density of dopamine-containing fibres in the area of the host caudate putamen surrounding the probe. Treatment with 0.05 mg/kg (subcutaneous) apomorphine did not affect extracellular dopamine recovered from the grafted striatum, while extracellular DA decreased by a maximum of 30% on the intact side. However, a subsequent injection of 0.5 mg/kg apomorphine produced a large decrease of the dopamine recovered from both the grafted (maximum 40% decrease) and intact striata (maximum 80% decrease). Both the low and the high dose of apomorphine reduced extracellular dopamine metabolite levels, a response which was essentially similar for both the intact and grafted sides. Finally, the dopamine reuptake blocker nomifensine (10−5M) added to the perfusion medium produced similar large increases in dopamine in perfusates collected from both grafted and intact striata, while 3,4-dihydroxyphenylacetic acid and homovanillic acid did not change.The results indicate that the dopamine-receptor-mediated autoregulatory control and dopamine reuptake, which normally operate in the nigrostriatal dopamine pathway, are also functioning in the intrastriatal nigral grafts although dopamine release from grafted neurons is less sensitive to apomorphine treatment. It is proposed that dopamine autoregulation and negative feedback is an important physiological mechanism for tonic regulation of dopamine graft function, and that this may be sufficient for the reinstatement of motoric and sensorimotoric behaviour by intrastriatal nigral grafts.