Robinson T E, Whishaw I Q
Department of Psychology, University of Michigan, Ann Arbor 48109.
Brain Res. 1988 May 31;450(1-2):209-24. doi: 10.1016/0006-8993(88)91560-0.
It has been hypothesized that striatal dopamine (DA) terminals undergo compensatory changes in response to partial damage of the mesostriatal DA system, which results in higher concentrations of DA in the extracellular space than would be predicted by DA concentrations in post-mortem tissue. But, this hypothesis has never been tested directly in vivo, and therefore, the present study was designed signed to do so. Microdialysis was used in freely moving rats to estimate the concentration of DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in striatal extracellular fluid; simultaneously from the hemisphere with unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra and from the intact hemisphere. It was found that following recovery from a 6-OHDA lesion, and during the resting state, the extracellular concentrations of DA were normal on the lesion side, even after that side was depleted of up to 99.0% of the DA measured in post-mortem tissue. Furthermore, the extracellular concentrations of DA were elevated in the intact hemisphere of animals with a greater than 95% DA depletion. In rats with a less than 95% DA depletion amphetamine (1.5 mg/kg) caused a large increase in the extracellular concentration of DA in both the lesion and intact hemispheres (intact greater than lesion), but in rats with a greater than 95% tissue DA depletion amphetamine only enhanced extracellular DA on the intact side; on the lesion side amphetamine produced a progressive decrease in extracellular DA to nondetectable levels. Animals rotated towards the lesion side. Unlike DA, the extracellular concentrations of DOPAC and HVA were greatly reduced on the lesion side, and the extent of the depletion was highly correlated with lesion size. It is concluded that following partial unilateral damage to mesostriatal DA projections there are massive changes in the remaining DA terminals that are sufficient to normalize the extracellular (and presumably synaptic) concentrations of DA. The normalization of extracellular DA concentrations seen after extensive (but incomplete) damage to the mesostriatal system must play a major role in the sparing and recovery of behavioral function that is so characteristics of this system. After extensive damage the capacity of the remaining DA neurons to respond to increased demand is limited, however, and this may explain why behavioral deficits can be reinstated by stimuli that challenge the system.
有假说认为，纹状体多巴胺（DA）终末会因中脑纹状体DA系统的部分损伤而发生代偿性变化，这导致细胞外空间中DA的浓度高于尸检组织中DA浓度所预测的水平。但是，这一假说从未在体内直接得到验证，因此，本研究旨在对此进行验证。在自由活动的大鼠中使用微透析技术来估计纹状体细胞外液中DA、二羟基苯乙酸（DOPAC）、高香草酸（HVA）和5-羟吲哚乙酸（5-HIAA）的浓度；同时从黑质单侧6-羟基多巴胺（6-OHDA）损伤的半球以及完整半球进行测量。结果发现，在6-OHDA损伤恢复后且处于静息状态时，损伤侧的DA细胞外浓度正常，即便该侧的DA含量比尸检组织中测得的DA含量减少了高达99.0%。此外，在DA耗竭超过95%的动物的完整半球中，DA的细胞外浓度升高。在DA耗竭低于95%的大鼠中，苯丙胺（1.5mg/kg）会使损伤半球和完整半球的DA细胞外浓度大幅增加（完整半球大于损伤半球），但在DA组织耗竭超过95%的大鼠中，苯丙胺仅增强了完整侧的细胞外DA；在损伤侧，苯丙胺使细胞外DA逐渐降低至无法检测的水平。动物向损伤侧旋转。与DA不同，损伤侧的DOPAC和HVA细胞外浓度大幅降低，且耗竭程度与损伤大小高度相关。结论是，中脑纹状体DA投射发生部分单侧损伤后，剩余DA终末会发生大量变化，足以使DA的细胞外（可能还有突触）浓度正常化。中脑纹状体系统受到广泛（但不完全）损伤后出现的细胞外DA浓度正常化现象，必定在该系统特有的行为功能的保留和恢复中起主要作用。然而，在广泛损伤后，剩余DA神经元对增加的需求作出反应的能力是有限的，这或许可以解释为什么行为缺陷会因挑战该系统的刺激而再次出现。
