Heterogeneity of electrically evoked dopamine release and reuptake in substantia nigra, ventral tegmental area, and striatum
Heterogeneity of electrically evoked dopamine release and reuptake in substantia nigra, ventral tegmental area, and striatum
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DOI：
10.1152/jn.1997.77.2.863
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发表时间：
1997-02-01
影响因子：
2.5
通讯作者：
Greenfield, SA
中科院分区：
文献类型：
--
作者：
Cragg, SJ;Rice, ME;Greenfield, SA
黑质腹侧被盖区（VTA）和黑质腹侧被盖区（SNc）释放的多巴胺（DA）可能介导突触外神经元信号。在体树突激活过程中获得的细胞外DA浓度（[DA]（o））将由释放位点的密度和DA摄取的性质决定。我们用碳纤维微电极和快速扫描循环伏安法评估了SNc、VTA和背侧纹状体中的这些因素，以监测豚鼠脑切片局部电刺激（10 Hz，5 s）期间的[DA]（o）。刺激的DA流出具有部位特异性，尾侧的[DA]（o）显著高于尾侧。（0.48 +/- 0.03 μ M，平均值+/- SE）比吻侧SNc（0.16 +/- 0.01 μ M），在其中间外侧范围内平均，VTA的[DA]（o）（0.74 ± 0.07 μ M）高于内侧SNc（0.43 ± 0.04 μ M）或外侧SNc（0.29 ± 0.05 μ M）。在整个SNc，诱发的[DA]（o）与酪氨酸羟化酶免疫反应细胞的密度呈正相关（r = 0.91）。通过摄取对诱发的[DA]（o）的调节也具有部位特异性。选择性DA摄取抑制剂GBR 12909显著增加尾侧SNc（至185 +/- 27%）和纹状体（408 +/- 24%）的诱发[DA]（o），但对吻侧SNc或VTA无影响。相反，去甲肾上腺素（NE）摄取抑制剂地昔帕明并没有改变尾侧SNc或纹状体中刺激的[DA]（o），但引起吻侧SNc（196 +/- 17%）和VTA（126 +/- 12%）的显著增强。帕罗西汀是一种选择性5-羟色胺摄取抑制剂，在任何测试区域几乎没有效果。对地昔帕明的位点特异性敏感性要求评价中脑多巴胺-β-羟化酶免疫反应性（D β H-ir）。D β H-ir阳性细丝的密度在吻侧SNc和VTA中比在尾侧SNc中更大，表明DA通过NE转运体在这些区域中清除。重要的是，D β H-ir在SNc吻侧的切片中最密集，其中没有检测到儿茶酚胺信号，并且没有观察到地昔帕明的增强，表明在任何检查的区域中缺乏NE对诱发释放的贡献。两者合计，这些数据证实，诱发体树突[DA]（o）取决于DA细胞密度和局部摄取特性。SNc和VTA的摄取效率低于纹状体。此外，GBR 12909对刺激的[DA]（o）的增强表明，树突的诱发释放不是通过逆转DA转运蛋白。最后，SNc和VTA内DA摄取的异质模式与帕金森病的退化模式一致：较不脆弱的DA细胞，例如，腹侧被盖区的细胞比尾侧SNc的更脆弱的细胞具有更少的DA摄取。
Somatodendritic dopamine (DA) released in substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) may mediate extrasynaptic neuronal signaling. The concentration of extracellular DA ([DA](o)) attained during somatodendritic activation will be governed by the density of release sites and properties of DA uptake. We evaluated these factors in SNc, VTA, and dorsal striatum with carbon-fiber microelectrodes and fast-scan cyclic voltammetry to monitor [DA](o) during local electrical stimulation (10 Hz, 5 s) in guinea pig brain slices. Stimulated DA efflux was site specific, with significantly higher [DA](o) in caudal (0.48 +/- 0.03 mu M, mean +/- SE) than rostral SNc (0.16 +/- 0.01 mu M), averaged over their mediolateral extents, and higher [DA](o) in VTA (0.74 +/- 0.07 mu M) than in medial (0.43 +/- 0.04 mu M) or lateral SNc (0.29 +/- 0.05 mu M), averaged rostrocaudally. Throughout SNc, evoked [DA](o) correlated positively (r = 0.91) with the density of tyrosine-hydroxylase-immunoreactive cells. Modulation of evoked [DA](o) by uptake was also site specific. The selective DA uptake inhibitor GBR 12909 significantly increased evoked [DA](o) in caudal SNc (to 185 +/- 27%) and striatum (408 +/- 24%), but had no effect in rostral SNc or VTA. Conversely, the norepinephrine (NE) uptake inhibitor desipramine did not alter stimulated [DA](o) in caudal SNc or striatum, but caused significant enhancement in rostral SNc (196 +/- 17%) and VTA (126 +/- 12%). Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor, had little effect in any region tested. Site-specific sensitivity to desipramine mandated evaluation of dopamine-beta-hydroxylase immunoreactivity (D beta H-ir) in midbrain. The density of filaments positive for D beta H-ir was greater in rostral SNc and VTA than in caudal SNc, suggesting DA clearance via the NE transporter in these regions. Importantly, D beta H-ir was most dense in sections rostral to SNc where no catecholamine signal was detected and no enhancement was observed with desipramine, indicating a lack of NE contribution to evoked release in any region examined. Taken together, these data confirmed that evoked somatodendritic [DA](o) depends on DA cell density and on local uptake properties. Uptake was less efficient in SNc and VTA than in striatum. Moreover, enhancement of stimulated [DA](o) by GBR 12909 demonstrated that evoked release from dendrites is not via reversal of the DA transporter. Lastly, the heterogeneous patterns of DA uptake within SNc and VTA were consistent with the pattern of degeneration in Parkinson's disease: less vulnerable DA cells, e.g., those in VTA, have less DA uptake than the more vulnerable cells of caudal SNc.