Hansard Matthew J, Smith Lance A, Jackson Michael J, Cheetham Sharon C, Jenner Peter
Neurodegenerative Disease Research Centre, Guy's, King's, and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom.
J Pharmacol Exp Ther. 2002 Dec;303(3):952-8. doi: 10.1124/jpet.102.039743.
Monoamine reuptake inhibitors that do not discriminate between the transporters for dopamine (DA), norepinephrine (NE), or 5-hydroxytryptamine (5-HT, serotonin) can reverse locomotor deficits and motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. DA reuptake inhibition is presumed to be primarily responsible, but the role played by inhibition of NE and 5-HT reuptake is unknown. We now evaluate the efficacy of a range of monoamine reuptake inhibitors either alone or in combination in MPTP-treated common marmosets to determine the actions required for effective antiparkinsonian activity. Monoamine reuptake inhibitors not discriminating between the DA, NE, and 5-HT transporters [1-[1-(3,4-dichlororphenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate (BTS 74 398) and nomifensine] reversed locomotor deficits and motor disability in MPTP-treated marmosets but bupropion was without effect. The selective DA reuptake inhibitor 1-(2-(bis-(4-fluorophenyl)-methoxy)ethyl)-4-(3-phenylpropyl) piperazine) dihydrochloride (GBR 12909) also reversed these motor deficits. The relative efficacy of the compounds (BTS 74 398 > GBR 12909 > nomifensine >> bupropion) paralleled their potency in inhibiting DA uptake in vitro and in vivo. In contrast, the selective NE reuptake inhibitor nisoxetine and the 5-HT reuptake inhibitor sertraline administered alone failed to improve motor function and tended to worsen the deficits. Coadministration of nisoxetine attenuated the improvement in motor deficits produced by GBR 12909. Coadministration of sertraline also abolished the reversal of motor deficits produced by GBR 12909. Coadministration of both sertraline and nisoxetine similarly abolished the improvement of motor deficits produced by GBR 12909. Molecules possessing potent DA reuptake inhibitory activity may be useful in the treatment of the motor symptoms of Parkinson's disease. In contrast, there seems to be no role for NE or 5-HT reuptake inhibitors, and they may impair antiparkinsonian activity mediated through dopaminergic mechanisms.
对多巴胺（DA）、去甲肾上腺素（NE）或5-羟色胺（5-HT，血清素）转运体无选择性的单胺再摄取抑制剂，可逆转1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的普通狨猴的运动功能障碍和运动残疾。推测DA再摄取抑制起主要作用，但NE和5-HT再摄取抑制所起的作用尚不清楚。我们现在评估一系列单胺再摄取抑制剂单独或联合使用对MPTP处理的普通狨猴的疗效，以确定有效抗帕金森病活性所需的作用。对DA、NE和5-HT转运体无选择性的单胺再摄取抑制剂[1-[1-(3,4-二氯苯基)环丁基]-2-(3-二氨基乙基氨基丙基硫代)乙酮单柠檬酸盐（BTS 74 398）和诺米芬辛]可逆转MPTP处理的狨猴的运动功能障碍和运动残疾，但安非他酮无效。选择性DA再摄取抑制剂1-(2-(双-(4-氟苯基)-甲氧基)乙基)-4-(3-苯基丙基)哌嗪二盐酸盐（GBR 12909）也可逆转这些运动功能障碍。这些化合物的相对疗效（BTS 74 398 > GBR 12909 > 诺米芬辛 >> 安非他酮）与其在体外和体内抑制DA摄取的效力平行。相比之下，选择性NE再摄取抑制剂尼索西汀和5-HT再摄取抑制剂舍曲林单独给药未能改善运动功能，且有使功能障碍加重的趋势。尼索西汀与GBR 12909联合给药减弱了其对运动功能障碍的改善作用。舍曲林与GBR 12909联合给药也消除了其对运动功能障碍的逆转作用。舍曲林和尼索西汀联合给药同样消除了GBR 12909对运动功能障碍的改善作用。具有强效DA再摄取抑制活性的分子可能对帕金森病运动症状的治疗有用。相比之下，NE或5-HT再摄取抑制剂似乎没有作用，且可能损害通过多巴胺能机制介导的抗帕金森病活性。
