EXTRACELLULAR CONCENTRATIONS OF DOPAMINE AND METABOLITES IN THE RAT CAUDATE AFTER ORAL-ADMINISTRATION OF A NOVEL CATECHOL-O-METHYLTRANSFERASE INHIBITOR RO 40-7592
EXTRACELLULAR CONCENTRATIONS OF DOPAMINE AND METABOLITES IN THE RAT CAUDATE AFTER ORAL-ADMINISTRATION OF A NOVEL CATECHOL-O-METHYLTRANSFERASE INHIBITOR RO 40-7592
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DOI：
10.1111/j.1471-4159.1992.tb08907.x
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发表时间：
1992-07-01
影响因子：
4.7
通讯作者：
DICHIARA, G
中科院分区：
文献类型：
--
作者：
ACQUAS, E;CARBONI, E;DICHIARA, G
采用经脑微透析法，在自由活动大鼠的背侧尾状核，观察了口服新型邻苯二酚氧甲基转移酶(COMT)抑制剂RO40-7592对多巴胺(DA)及其代谢产物二羟基苯乙酸(DOPAC)和高香草酸(HVA)胞外浓度的影响。RO 40-7592(3.0、7.5和30 mg/kg P.O.)剂量为7.5 mg/kg和30 mg/kg时，DOPAC产量增加。但它未能增加DA的产量。L-β-3，4-二羟基苯丙氨酸(L-DOPA，20 mg/kg和50 mg/kg P.O.)使用多巴脱羧酶抑制剂(苯丝肼)时，透析液中多巴酚A和多巴比妥酸的产量均增加，但不能显著改变透析液中细胞外多巴胺的浓度；L-多巴+多塞肼与RO40-7592(30 mg/kg P.O.)联合使用。结果大大增加了发展援助的产出。RO 40-7592可拮抗L-多巴诱导的HVA产量增加，并明显增强DOPAC产量的增加。为了研究细胞外DA浓度的增加在多大程度上与外来释放有关，我们测试了河豚毒素(TTX)的敏感性。在Ringer中加入TTX，虽然在没有L-DOPA的情况下取消了DA的输出，但在L-DOPA+Ro40-7592时部分减少了DA的输出，在L-DOPA没有COMT抑制剂的情况下更是如此。本研究结果提示，COMT代谢可调节外源性给药L-多巴形成的细胞外DA浓度，但不能调节内源性DA的浓度。因此，COMT的抑制不仅通过抑制其外周代谢(转化为3-甲氧基-多巴)，而且还通过抑制其活性代谢物DA在脑内的代谢而增强L-多巴的作用。
The effect of the systemic administration of a novel, orally active, catechol-O-methyltransferase (COMT) inhibitor, Ro 40-7592, on the in vivo extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), was studied by transcerebral microdialysis in the dorsal caudate of freely moving rats. Ro 40-7592 (at doses of 3.0, 7.5, and 30 mg/kg p.o.) elicited a marked and long-lasting reduction of HVA, and at doses of 7.5 and 30 mg/kg, an increase of DOPAC output. but it failed to increase DA output. The administration of L-beta-3,4-dihydroxyphenylalanine (L-DOPA, 20 and 50 mg/kg p.o.) with a DOPA decarboxylase inhibitor (benserazide) increased both HVA and DOPAC output, but failed to modify significantly extracellular DA concentrations in dialysates; in contrast, combined administration of L-DOPA + benserazide with Ro 40-7592 (30 mg/kg p.o.) resulted in a significant increase in DA output. Ro 40-7592 prevented the L-DOPA-induced increase in HVA output and markedly potentiated the increase in DOPAC output. To investigate to what extent the increase in extracellular DA concentrations was related to an exocitotic release, tetrodotoxin (TTX) sensitivity was tested. Addition of TTX to Ringer, although abolishing DA output in the absence of L-DOPA, partially reduced it in the presence of L-DOPA + Ro 40-7592 and even more so after L-DOPA without the COMT inhibitor. The results of the present study suggest that metabolism through COMT regulates extracellular concentrations of DA formed from exogenously administered L-DOPA but not of endogenous DA. Therefore, inhibition of COMT results in a potentiation of L-DOPA effects not only by inhibition of its peripheral metabolism (conversion to 3-methoxy-DOPA), but also by inhibition of the metabolism of its active metabolite, DA, in the brain.