Previous studies have pointed out that l-DOPA can interact with D1 or D2 receptors independent of its conversion to endogenous dopamine. The present study was set to investigate whether l-DOPA modulates dopamine release from striatal nerve terminals, using a preparation of synaptosomes preloaded with [³H]DA. Levodopa (1 µM) doubled the K⁺-induced [³H]DA release whereas the D2/D3 receptor agonist pramipexole (100 nM) inhibited it. The l-DOPA-evoked facilitation was mimicked by the D1 receptor agonist SKF38393 (30–300 nM) and prevented by the D1/D5 antagonist SCH23390 (100 nM) but not the DA transporter inhibitor GBR12783 (300 nM) or the aromatic l-amino acid decarboxylase inhibitor benserazide (1 µM). Higher l-DOPA concentrations (10 and 100 µM) elevated spontaneous [³H]DA efflux. This effect was counteracted by GBR12783 but not SCH23390. Binding of [³H]SCH23390 in synaptosomes (in test tubes) revealed a dense population of D1 receptors (2105 fmol/mg protein). Both SCH23390 and SKF38393 fully inhibited [³H]SCH23390 binding (Ki 0.42 nM and 29 nM, respectively). l-DOPA displaced [³H]SCH23390 binding maximally by 44% at 1 mM. This effect was halved by addition of GBR12935 and benserazide. We conclude that l-DOPA facilitates exocytotic [³H]DA release through SCH23390-sensitive D1 receptors, independent of its conversion to DA. It also promotes non-exocytotic [³H]DA release, possibly via conversion to DA and reversal of DA transporter. These data confirm that l-DOPA can directly interact with dopamine D1 receptors and might extend our knowledge of the neurobiological mechanisms underlying l-DOPA clinical effects.

以前的研究已经指出，l- DOPA 可以与 D1 或 D2 受体相互作用，而与其转化为内源性多巴胺无关。本研究旨在使用预加载 [ ³ H]DA的突触体制剂研究l -DOPA 是否调节纹状体神经末梢的多巴胺释放。左旋多巴 (1 µM) 使 K ⁺诱导的 [ ³ H]DA 释放加倍，而 D2/D3 受体激动剂普拉克索 (100 nM) 抑制它。L -DOPA 诱发的促进作用由 D1 受体激动剂 SKF38393 (30–300 nM) 模拟，并由 D1/D5 拮抗剂 SCH23390 (100 nM) 而不是 DA 转运蛋白抑制剂 GBR12783 (300 nM) 或芳香族l-氨基酸脱羧酶抑制剂苄丝肼 (1 µM)。较高的l- DOPA 浓度（10 和 100 µM）会增加自发的 [ ³ H]DA 流出。这种影响被 GBR12783 而不是 SCH23390 抵消。[ ³ H]SCH23390 在突触体中的结合（在试管中）揭示了密集的 D1 受体群（2105 fmol/mg 蛋白质）。SCH23390 和 SKF38393 均完全抑制 [ ³ H]SCH23390 结合（Ki 分别为 0.42 nM 和 29 nM）。l -DOPA 在 1 mM 时将 [ ³ H]SCH23390 的结合最多置换了 44%。通过添加 GBR12935 和苄丝肼，这种效果减半。我们得出结论，l -DOPA 促进胞吐 [ ³H]DA 通过 SCH23390 敏感的 D1 受体释放，与其转化为 DA 无关。它还促进非胞吐的 [ ³ H]DA 释放，可能通过转化为 DA 和 DA 转运蛋白的逆转。这些数据证实了l- DOPA 可以直接与多巴胺 D1 受体相互作用，并可能扩展我们对l- DOPA 临床效应背后的神经生物学机制的认识。