Bennett B A, Hyde C E, Pecora J R, Clodfelter J E
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1083.
J Neurochem. 1993 Apr;60(4):1444-52. doi: 10.1111/j.1471-4159.1993.tb03307.x.
The potent reinforcing effects of methamphetamine and cocaine are thought to be mediated by their interactions with CNS dopamine neurons. Both stimulants share the ability to block dopamine uptake potently, and methamphetamine can release cytoplasmic dopamine as well. There is also abundant evidence demonstrating the neurotoxic effects of methamphetamine. There are, however, limited studies that attempt to discern the neurotoxic mechanisms of these agents. The purpose of the present study was to characterize and compare the chronic in vitro effects of methamphetamine, cocaine, and the dopamine uptake blocker, mazindol, on cultured fetal mesencephalic dopamine neurons. Our studies examined biochemical mechanisms to evaluate the contribution of reuptake blockade versus release of dopamine. Using a dispersed cell preparation of fetal mesencephalon, cultures were treated for 5 days with the three uptake blockers. Dopamine function was assessed by measuring high-affinity [3H]dopamine uptake and by examining cultures for the presence of tyrosine hydroxylase-immunopositive neurons. Nonspecific neurotoxicity was assessed by staining for neuron-specific enolase and measuring lactate dehydrogenase activity. The results indicate that repeated administration of high concentrations of methamphetamine (10(-4) and 10(-3) M) caused a generalized neurotoxicity whereas the effects of 10(-5) M methamphetamine appeared to be specific to dopamine cells. Likewise, treatment of the cultures with mazindol (10(-6) M) resulted in reduced dopamine uptake while not significantly affecting neuron-specific enolase or tyrosine hydroxylase immunostaining. On the other hand, repeated exposure to cocaine (10(-5) and 10(-4) M) did not alter dopaminergic function in these cultures. The different mechanisms of action of these stimulants may explain the differences in neurotoxic potency of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
甲基苯丙胺和可卡因的强效强化作用被认为是通过它们与中枢神经系统多巴胺神经元的相互作用介导的。这两种兴奋剂都具有强力阻断多巴胺摄取的能力，甲基苯丙胺还能释放细胞质中的多巴胺。也有大量证据证明甲基苯丙胺的神经毒性作用。然而，试图辨别这些药物神经毒性机制的研究有限。本研究的目的是描述和比较甲基苯丙胺、可卡因以及多巴胺摄取阻断剂马吲哚对培养的胎儿中脑多巴胺神经元的慢性体外作用。我们的研究检测了生化机制，以评估再摄取阻断与多巴胺释放的作用。使用胎儿中脑的分散细胞制备物，用这三种摄取阻断剂对培养物处理5天。通过测量高亲和力[3H]多巴胺摄取以及检查培养物中酪氨酸羟化酶免疫阳性神经元的存在来评估多巴胺功能。通过对神经元特异性烯醇化酶进行染色并测量乳酸脱氢酶活性来评估非特异性神经毒性。结果表明，重复给予高浓度的甲基苯丙胺（10^(-4)和10^(-3) M）会导致普遍的神经毒性，而10^(-5) M甲基苯丙胺的作用似乎对多巴胺细胞具有特异性。同样，用马吲哚（10^(-6) M）处理培养物会导致多巴胺摄取减少，而对神经元特异性烯醇化酶或酪氨酸羟化酶免疫染色没有显著影响。另一方面，重复暴露于可卡因（10^(-5)和10^(-4) M）并未改变这些培养物中的多巴胺能功能。这些兴奋剂不同的作用机制可能解释了这些化合物在神经毒性强度上的差异。（摘要截短于250字）
