Sanders-Bush E, Bushing J A, Sulser F
J Pharmacol Exp Ther. 1975 Jan;192(1):33-41.
Earlier studies from our laboratory have demonstrated a marked reduction in the brain level of 5-hydroxytryptamine (5-HT) and in the activity of tryptophan hydroxylase which persists for several weeks after a single dose of 10 mg/kg of p-chloroamphetamine (PCA). In the present study, equally long-lasting decreases were found after the administration of 5 mg/kg of PCA. p-Chloromethamphetamine also caused long-lasting reductions in the level of 5-HT and the activity of tryptophan hydroxylase in brain, whereas the effects of fenfluramine had disappeared 2 weeks after injection. The ability of brain synaptosomes to take up 5-HT was markedly reduced following doses of 2, 5 and 10 mg/kg of PCA. The in vitro addition of PCA to synaptosomal fractions markedly reduced the uptake of dopamine and norepinephrine; however, only a 30% reduction in the uptake of these amines was found in synaptosomes prepared from brains of rats treated with PCA. The effects on catecholamine uptake disappeared within 1 day after injection. In contrast, the time course of recovery of the synaptosomal uptake capacity for 5-HT followed a pattern similar to that found for the recovery of the level of 5-HT and the activity of tryptophan hydroxylase, with a 50% reduction still present 3 months after the injection of 10 mg/kg of PCA. The greatest reductions of 5-HT, tryptophan hydroxylase activity and synaptosomal uptake were found in the midbrain, hippocampus and striatum with less pronounced effects in the hypothalamus, medulla-pons and spinal cord. At both 1 and 14 days after injection of 5 and 7.5 mg/kg of PCA, tryptophan hydroxylase activity in whole brain was reduced by 50% or more; however, 4 days after treatment the activity of the enzyme was reduced only slightly or not at all. The results indicate that different independent mechanisms are responsible for the initial, reversible and the prolonged, irreversible effects of PCA on serotonergic neurons.
我们实验室早期的研究表明，单次注射10mg/kg对氯苯丙胺（PCA）后，大脑中5-羟色胺（5-HT）水平和色氨酸羟化酶活性显著降低，并持续数周。在本研究中，注射5mg/kg的PCA后也发现了同样持久的降低。对氯甲基苯丙胺也导致大脑中5-HT水平和色氨酸羟化酶活性的持久降低，而氟苯丙胺的作用在注射后2周消失。注射2、5和10mg/kg的PCA后，脑突触体摄取5-HT的能力显著降低。在体外将PCA添加到突触体组分中，显著降低了多巴胺和去甲肾上腺素的摄取；然而，在用PCA处理的大鼠大脑制备的突触体中，这些胺的摄取仅降低了30%。对儿茶酚胺摄取的影响在注射后1天内消失。相比之下，突触体对5-HT摄取能力的恢复时间进程与5-HT水平和色氨酸羟化酶活性的恢复模式相似，注射10mg/kg的PCA后3个月，摄取能力仍降低50%。在中脑、海马和纹状体中发现5-HT、色氨酸羟化酶活性和突触体摄取的降低最为显著，在下丘脑、延髓-脑桥和脊髓中的影响则不太明显。注射5和7.5mg/kg的PCA后1天和14天，全脑中色氨酸羟化酶活性降低了50%或更多；然而，治疗后4天，该酶的活性仅略有降低或根本没有降低。结果表明，PCA对5-羟色胺能神经元的初始、可逆和长期、不可逆作用是由不同的独立机制引起的。
