Treseder S A, Rose S, Jenner P
Neurodegenenerative Disease Research Centre, Division of Pharmacology & Therapeutics, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London, Guy's Campus, London, SE1 1UL, UK.
Eur J Neurosci. 2001 Jan;13(1):162-70. doi: 10.1046/j.0953-816x.2000.01370.x.
The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. However, the effects of NSD-1015 on L-DOPA-induced motor activity are unclear as both increases and decreases have been reported. We now investigate the effects of NSD-1015 on L-DOPA-induced contralateral circling behaviour in 6-OHDA-lesioned rats and on striatal levels of L-DOPA, 3-O-methyl-DOPA (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) using microdialysis techniques. NSD-1015 (50-200 mg/kg i.p.) inhibited AADC activity both in the liver and striatum of normal rats. Administration of NSD-1015 (50-200 mg/kg i.p.), delayed the onset of circling produced by administration of L-DOPA (25 mg/kg i.p.) and carbidopa (12.5 mg/kg i. p.), suggesting blockade of central AADC activity. However, the duration of the L-DOPA-induced circling was prolonged and overall no inhibition of circling behaviour occurred. L-DOPA (25 mg/kg i.p.) plus carbidopa (12.5 mg/kg i.p.) increased extracellular levels of L-DOPA, 3-OMD, dopamine, DOPAC and HVA in the 6-OHDA-lesioned striatum. Pretreatment of rats with the central AADC inhibitor, NSD-1015 (100 mg/kg i.p.), potentiated the increase in dialysate levels of L-DOPA and 3-OMD. However, it did not reduce striatal dopamine levels in the 6-OHDA-lesioned hemisphere, which were elevated following L-DOPA administration. The increases in DOPAC and HVA levels were abolished by NSD-1015 pretreatment. These results suggest that, while NSD-1015 blocks central AADC activity, it also acts as a monoamine oxidase inhibitor so maintaining striatal dopamine concentration by reducing dopamine metabolism. NSD-1015, therefore, may not be an appropriate tool for the study of brain AADC activity and for assessing the neuromodulatory role of L-DOPA.
中枢作用的芳香族氨基酸多巴脱羧酶（AADC）抑制剂3-羟基苄基肼（NSD-1015）被广泛用于研究左旋多巴的类神经递质作用。然而，NSD-1015对左旋多巴诱导的运动活动的影响尚不清楚，因为既有增加也有减少的报道。我们现在使用微透析技术研究NSD-1015对6-羟基多巴胺（6-OHDA）损伤大鼠中左旋多巴诱导的对侧转圈行为以及纹状体中左旋多巴、3-O-甲基多巴（3-OMD）、多巴胺、二羟基苯乙酸（DOPAC）和高香草酸（HVA）水平的影响。NSD-1015（腹腔注射50-200mg/kg）抑制正常大鼠肝脏和纹状体中的AADC活性。给予NSD-1015（腹腔注射50-200mg/kg）可延迟左旋多巴（腹腔注射25mg/kg）和卡比多巴（腹腔注射12.5mg/kg）诱导的转圈发作，提示中枢AADC活性被阻断。然而，左旋多巴诱导的转圈持续时间延长，总体上未出现对转圈行为的抑制。左旋多巴（腹腔注射25mg/kg）加卡比多巴（腹腔注射12.5mg/kg）可增加6-OHDA损伤纹状体中左旋多巴、3-OMD、多巴胺、DOPAC和HVA的细胞外水平。用中枢AADC抑制剂NSD-1015（腹腔注射100mg/kg）预处理大鼠可增强透析液中左旋多巴和3-OMD水平的升高。然而，它并未降低6-OHDA损伤半球中左旋多巴给药后升高的纹状体多巴胺水平。NSD-1015预处理消除了DOPAC和HVA水平的升高。这些结果表明，虽然NSD-1015阻断中枢AADC活性，但它也作为单胺氧化酶抑制剂，通过减少多巴胺代谢来维持纹状体多巴胺浓度。因此，NSD-1015可能不是研究脑AADC活性和评估左旋多巴神经调节作用的合适工具。
