Molliver M E, Berger U V, Mamounas L A, Molliver D C, O'Hearn E, Wilson M A
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Ann N Y Acad Sci. 1990;600:649-61; discussion 661-4. doi: 10.1111/j.1749-6632.1990.tb16916.x.
The cytotoxic effects of amphetamine derivatives were studied by immunocytochemistry to identify the cellular compartments affected by these drugs, to obtain morphologic evidence of neuronal degeneration, and to assess the potential for regeneration. The substituted amphetamines, MDA, MDMA, PCA, and fenfluramine, all release serotonin and cause acute depletion of 5-HT from most axon terminals in forebrain. (1) Unequivocal signs of axon degeneration were seen at 36-48 hour survivals: 5-HT axons exhibited increased caliber, huge, swollen varicosities, fragmentation, and dilated proximal axon stumps. (2) Fine 5-HT axon terminals were persistently lost after drug administration, while beaded axons and raphe cell bodies were spared. These two types of 5-HT axons, which arise from separate raphe nuclei and form distinct ascending projections, are differentially vulnerable to psychotropic drugs. (3) From 2-8 months after treatment, there was progressive serotonergic re-innervation of neocortex along a fronto-occipital gradient. Longitudinal 5-HT axons grew into layers I and VI from rostral to caudal, before sprouting into middle cortical layers; this bilaminar pattern of growth simulates perinatal development of 5-HT innervation. This study demonstrates differential vulnerability of 5-HT projections, evidence for axonal degeneration, and sprouting of 5-HT axons leading to re-innervation of forebrain. While the sprouting axons are anatomically similar to the type that was damaged, it is not known whether a normal pattern of innervation is re-established.
通过免疫细胞化学研究了苯丙胺衍生物的细胞毒性作用，以确定受这些药物影响的细胞区室，获得神经元变性的形态学证据，并评估再生潜力。取代苯丙胺、3,4-亚甲基二氧基苯丙胺（MDA）、3,4-亚甲基二氧基甲基苯丙胺（MDMA）、对氯苯丙胺（PCA）和芬氟拉明，均能释放5-羟色胺并导致前脑大多数轴突终末的5-羟色胺急性耗竭。（1） 在存活36 - 48小时时可见明确的轴突变性迹象：5-羟色胺轴突表现出管径增粗、巨大肿胀的曲张、断裂以及近端轴突残端扩张。（2） 给药后细的5-羟色胺轴突终末持续丢失，而成串珠状的轴突和中缝核细胞体则未受影响。这两种类型的5-羟色胺轴突，分别起源于不同的中缝核并形成不同的上行投射，对精神药物的易损性不同。（3） 治疗后2 - 8个月，新皮质沿额枕梯度出现渐进性的5-羟色胺能再支配。纵向的5-羟色胺轴突从吻侧到尾侧生长到I层和VI层，然后向皮质中间层发芽；这种双层层状生长模式模拟了5-羟色胺能神经支配的围产期发育。本研究证明了5-羟色胺投射的不同易损性、轴突变性的证据以及5-羟色胺轴突发芽导致前脑再支配。虽然发芽的轴突在解剖学上与受损的轴突相似，但尚不清楚是否重新建立了正常的神经支配模式。
