Fisher A, Biggs C S, Eradiri O, Starr M S
Department of Pharmacology, School of Pharmacy, London, UK.
Neuroscience. 2000;95(1):97-111. doi: 10.1016/s0306-4522(99)00406-6.
The comparative effects of L-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25-200 mg/kg) dose-dependently inhibited the activity of aromatic L-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25-50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100-200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 microM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25-100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D1 > D2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.
在利血平处理的大鼠中研究了L-3,4-二羟基苯丙氨酸(L-DOPA)对多巴胺合成、释放及行为的比较效应。急性给予L-DOPA(25 - 200mg/kg)剂量依赖性地抑制黑质和纹状体中芳香族L-氨基酸脱羧酶(AADC)的活性。抗帕金森病药物布地品(10mg/kg)和金刚烷胺(40mg/kg)增强了这些区域的AADC活性,并预防或逆转了L-DOPA对AADC的抑制作用。双探针透析显示,低剂量的L-DOPA(25 - 50mg/kg)剂量依赖性地刺激黑质和纹状体中多巴胺和3,4-二羟基苯乙酸(DOPAC)的释放,而高剂量的L-DOPA(100 - 200mg/kg)完全抑制多巴胺的释放,但不抑制DOPAC的释放。通过探针给予舒必利(50μM)可拮抗25mg/kg L-DOPA引起的多巴胺释放,但极大地促进了200mg/kg L-DOPA引起的释放。多巴胺释放被中枢作用的AADC抑制剂NSD 1015阻断,但被中枢AADC激活剂布地品促进。在行为测试中,L-DOPA(加苄丝肼,50mg/kg)仅在200mg/kg时逆转运动不能,而在25 - 100mg/kg时则不能。用NSD 1015(100mg/kg)或布地品(10mg/kg)预处理可显著增强阈剂量L-DOPA(100mg/kg)的运动刺激作用。NSD 1015(100mg/kg)和苄丝肼(50mg/kg)联合使用比单独使用任何一种抑制剂更有效地增强L-DOPA的行为。NSD 1015促进的L-DOPA行为被舒必利(100mg/kg)拮抗,而不被SCH 23390(1mg/kg)拮抗,而布地品促进的L-DOPA行为被SCH 23390完全拮抗,仅被舒必利部分拮抗。这些结果表明,在利血平化大鼠中,具有行为活性剂量的L-DOPA并未伴随细胞外多巴胺的显著增加,因此可能不是由多巴胺介导的。我们提出,L-DOPA能够直接刺激多巴胺D2受体以及可能的非多巴胺受体,从而在突触前抑制多巴胺外流并在突触后促进运动激活。L-DOPA对运动行为的刺激作用,优先由D1>D2受体介导,表明L-DOPA在没有可检测到的多巴胺释放的情况下也可能产生类似多巴胺的反应。这些发现被纳入利血平化大鼠中L-DOPA作用的新模型,并讨论了它们对我们理解帕金森病中L-DOPA的可能意义。