Biggs C S, Starr M S
Department of Pharmacology, The School of Pharmacy, London, UK.
Synapse. 1999 Oct;34(1):36-46. doi: 10.1002/(SICI)1098-2396(199910)34:1<36::AID-SYN5>3.0.CO;2-G.
The purpose of this study was to determine if systemic treatment with the antiparkinsonian drug budipine was capable of influencing the release of dopamine newly synthesised from L-DOPA in the substantia nigra and corpus striatum of the monoamine-depleted rat. Dual probe microdialysis was therefore employed in freely moving animals pretreated with reserpine (4 mg/kg i.p. 18-20 h earlier) and alpha-methyl-p-tyrosine (200 mg/kg i.p. 45 min earlier). Budipine (10 mg/kg i.p.) alone evoked a small but significant increase in basal dopamine efflux in nigra, though not in striatum, but did not affect the spontaneous outputs of DOPAC, 5-HT, or 5-HIAA in either structure. A threshold amount of L-DOPA (25 mg/kg i.p.) stimulated the release of dopamine, DOPAC, and 5-HT (but not 5-HIAA), both in nigra and striatum. The L-DOPA-induced releases of dopamine and DOPAC were greatly accentuated by pretreatment with budipine (10 mg/kg i.p. 45 min earlier), which delayed rather than potentiated the nigral and striatal effluxes of 5-HT. A higher dose of L-DOPA (100 mg/kg i.p.) did not significantly raise the outputs of dopamine or 5-HT, but greatly magnified that of DOPAC. In these experiments, pretreatment with budipine (10 mg/kg i.p.) facilitated the formation of DOPAC from L-DOPA, without increasing the extracellular concentration of dopamine. We conclude from these findings that budipine, at a therapeutically relevant dose, potentiates the release of dopamine newly synthesised from L-DOPA from either end of the nigrostriatal dopamine axis. This effect of budipine could be related to the drug's recently described ability to increase the activity of the converting enzyme, aromatic L-amino acid decarboxylase, and could explain the clinical efficacy of budipine as an adjunct to L-DOPA therapy of Parkinson's disease in man. The significance of 5-HT release to the antiparkinsonian L-DOPA, and the delay in this release caused by budipine, remain to be established.
本研究的目的是确定使用抗帕金森病药物布地品进行全身治疗是否能够影响单胺耗竭大鼠黑质和纹状体内由左旋多巴新合成的多巴胺的释放。因此，在自由活动的动物中采用双探针微透析技术，这些动物预先接受了利血平（4 mg/kg腹腔注射，提前18 - 20小时）和α-甲基-对-酪氨酸（200 mg/kg腹腔注射，提前45分钟）的处理。单独使用布地品（10 mg/kg腹腔注射）可使黑质中基础多巴胺外流有小幅但显著的增加，而纹状体中则无此现象，但对这两个结构中3,4-二羟基苯乙酸（DOPAC）、5-羟色胺（5-HT）或5-羟吲哚乙酸（5-HIAA）的自发输出量均无影响。阈剂量的左旋多巴（25 mg/kg腹腔注射）可刺激黑质和纹状体中多巴胺、DOPAC和5-HT（但不包括5-HIAA）的释放。预先使用布地品（10 mg/kg腹腔注射，提前45分钟）可显著增强左旋多巴诱导的多巴胺和DOPAC的释放，同时延迟而非增强5-HT在黑质和纹状体中的外流。更高剂量的左旋多巴（100 mg/kg腹腔注射）并未显著提高多巴胺或5-HT的输出量，但极大地放大了DOPAC的输出量。在这些实验中，预先使用布地品（10 mg/kg腹腔注射）促进了由左旋多巴形成DOPAC，而未增加细胞外多巴胺浓度。从这些发现中我们得出结论，在治疗相关剂量下，布地品可增强黑质纹状体多巴胺轴两端由左旋多巴新合成的多巴胺的释放。布地品的这种作用可能与该药物最近被描述的增加转化酶芳香族L-氨基酸脱羧酶活性的能力有关，并且可以解释布地品作为左旋多巴治疗人类帕金森病辅助药物的临床疗效。5-HT释放对抗帕金森病左旋多巴的意义以及布地品引起的这种释放延迟仍有待确定。
