Goulet M, Morissette M, Grondin R, Falardeau P, Bédard P J, Rostène W, Di Paolo T
Faculty of Pharmacy, Laval University, Québec, Qc, Canada.
Synapse. 1999 Jun 1;32(3):153-64. doi: 10.1002/(SICI)1098-2396(19990601)32:3<153::AID-SYN2>3.0.CO;2-X.
The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was investigated. The MPTP lesion induced a marked depletion of DA (90% or more vs. control) in the caudate nucleus and putamen. The densities of NT agonist binding sites labeled with [125I]NT and the NT antagonist binding sites labeled with [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys. Levocabastine did not compete with high affinity for [125I]NT binding in the monkey cingulate cortex, suggesting that only one class of NT receptors was labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding sites (-92% vs. Control) was observed in the striatum of MPTP-monkeys and an important loss of DAT mRNA(-86% vs. Control) was observed in substantia nigra. Treatments for 1 month with either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT and DAT binding sites or DAT mRNA levels. The decrease of striatal NT binding sites was less than expected from the decrease of DA content in this nucleus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervation, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density.
研究了用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）使多巴胺（DA）黑质纹状体通路失神经支配对猕猴（食蟹猴）基底神经节中神经降压素（NT）受体和DA转运体（DAT）的影响。MPTP损伤导致尾状核和壳核中DA显著耗竭（与对照组相比减少90%或更多）。用[125I]NT标记的NT激动剂结合位点密度和用[3H]SR142948A标记的NT拮抗剂结合位点密度在MPTP处理的猕猴的尾状核-壳核中减少了一半。此外，用[125I]NT和[3H]SR142948A标记的结合位点密度在MPTP处理的猕猴的黑质中显著降低（分别为-77%和-63%）。左卡巴斯汀在猕猴扣带回皮质中对[125I]NT结合没有高亲和力竞争，这表明在猴脑中仅标记了一类NT受体。在MPTP处理的猕猴的纹状体中观察到[3H]GBR1293 DAT结合位点广泛减少（与对照组相比为-92%），并且在黑质中观察到DAT mRNA大量丢失（与对照组相比为-86%）。用D1激动剂SKF-82958（3mg/kg/天）或D2激动剂卡麦角林（0.25mg/kg/天）治疗1个月对损伤诱导的NT和DAT结合位点或DAT mRNA水平的降低没有影响。纹状体NT结合位点的减少低于该核中DA含量减少所预期的，这表明NT受体仅部分定位于黑质纹状体多巴胺能投射上。这些数据还表明，在严重的DA去神经支配下，用D1或D2 DA激动剂治疗不会调节NT受体和DAT密度。
