Rots N Y, Cools A R, Bérod A, Voorn P, Rostène W, de Kloet E R
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, University of Leiden, The Netherlands.
Brain Res. 1996 Feb 26;710(1-2):189-96. doi: 10.1016/0006-8993(95)01379-2.
From a Wistar population two rat lines were generated using as criterion the behavioral response to the dopamine agonist apomorphine. Rats of the apomorphine-susceptible (apo-sus) line revealed a vigorous gnawing response to apomorphine administration while the other rat line, the apomorphine-unsusceptible (apo-unsus) line, was selected for lack of response to the drug. In the present study using the 12th and 13th generation of these genetically selected lines, we have investigated whether this difference in apomorphine responsiveness was correlated with changes in dopamine neurochemistry. Therefore, we measured tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, as well as dopamine D1 and D2 receptor mRNA levels in discrete brain regions by in situ hybridization. Dopamine (D2/D3) receptor binding was assessed with [125I]iodosulpride in a membrane binding assay and by quantitative autoradiography on tissue sections. [3H]SCH 23390 was used to analyze D1 receptor binding. Apo-sus rats displayed significantly higher TH mRNA levels in the A9 cell group of the substantia nigra pars compacta and in the A12 cell group of the arcuate nucleus. No difference was found in the A10 cell group of the VTA and the A6 cell group of the locus coeruleus. The density of D2/3 binding sites as well as D1 receptor mRNA levels in the striatal projection area of the A9 substantia nigra neurons, were significantly elevated in apo-sus rats. Dopamine D2 receptor mRNA and D1 receptor binding levels in caudate putamen and nucleus accumbens, however, were similar in rats of both lines. In conclusion, high apomorphine susceptibility is related to a potentially enhanced dopamine responsiveness selective for the nigrostriatal and tuberoinfundibular pathways.
从Wistar种群中，依据对多巴胺激动剂阿扑吗啡的行为反应这一标准培育出了两个大鼠品系。阿扑吗啡敏感（apo-sus）品系的大鼠在注射阿扑吗啡后表现出强烈的啃咬反应，而另一个大鼠品系，即阿扑吗啡不敏感（apo-unsus）品系，则因对该药物无反应而被挑选出来。在本研究中，我们使用这些经过基因选择的品系的第12代和第13代，调查了阿扑吗啡反应性的这种差异是否与多巴胺神经化学的变化相关。因此，我们通过原位杂交测量了多巴胺合成中的限速酶酪氨酸羟化酶（TH），以及离散脑区中多巴胺D1和D2受体mRNA水平。在膜结合试验中使用[125I]碘舒必利并通过对组织切片进行定量放射自显影来评估多巴胺（D2/D3）受体结合。使用[3H]SCH 23390来分析D1受体结合。Apo-sus大鼠在黑质致密部的A9细胞群和弓状核的A12细胞群中显示出显著更高的TH mRNA水平。在腹侧被盖区的A10细胞群和蓝斑的A6细胞群中未发现差异。在apo-sus大鼠中，A9黑质神经元纹状体投射区域的D2/3结合位点密度以及D1受体mRNA水平显著升高。然而，两个品系大鼠的尾状壳核和伏隔核中的多巴胺D2受体mRNA和D1受体结合水平相似。总之，高阿扑吗啡敏感性与黑质纹状体和结节漏斗途径选择性的潜在增强的多巴胺反应性有关。
