Appel N M, Contrera J F, De Souza E B
Laboratory of Neurobiology, National Institute on Drug Abuse Addiction Research Center, Baltimore, Maryland.
J Pharmacol Exp Ther. 1989 Jun;249(3):928-43.
Fenfluramine is an amphetamine derivative which is used primarily as an anorectic agent in the treatment of obesity. High doses of fenfluramine have been reported to cause long-term decreases in brain serotonin (5-HT) levels and density of high-affinity 5-HT uptake sites, actions characteristic of a "neurotoxic" effect of the drug. In view of these neurochemical changes, we used immunocytochemistry to assess, in detail, the effects of fenfluramine treatment on the morphology and density of 5-HT-like immunoreactive neurons in rat brain. Twelve to 18 hr after high dose dl-fenfluramine HCl treatment (24 mg/kg s.c., twice daily for 4 days), there was a profound regional decrease in density of fine-caliber 5-HT-like immunoreactive fibers and terminals in brain. This effect was especially apparent in cerebral cortex, hippocampus, cerebellum and striatum and less striking decreases were noted in septum, locus ceruleus and hypothalamus. On the other hand, 5-HT-like immunoreactive somata in midbrain nuclei and fibers and terminals in spinal cord appeared unaffected after fenfluramine treatment. Remaining 5-HT-like immunoreactive fibers and terminals displayed morphology characteristic of degenerating axons (thickening, swollen varicosities and fragmentation). Two weeks after the 4-day treatment regimen, patterns of 5-HT-like immunostaining appeared similar to those noted immediately (i.e., 18 hr) after drug treatment; however, the presence of grossly deformed fibers and terminals seen shortly after drug treatment was lacking. Tyrosine hydroxylase-like immunoreactivity, used to assess changes in catecholamine-containing neurons, appeared unaffected by drug treatment. These data suggest that, in rats, high s.c. doses of fenfluramine may be neurotoxic to some 5-HT-like immunoreactive axons and terminals. The relevance of these observations to the continued therapeutic use in humans of smaller p.o. doses of fenfluramine remains to be determined.
芬氟拉明是一种苯丙胺衍生物，主要用作减肥药来治疗肥胖症。据报道，高剂量的芬氟拉明会导致大脑中血清素（5-羟色胺，5-HT）水平和高亲和力5-HT摄取位点密度的长期降低，这些是该药物“神经毒性”作用的特征性表现。鉴于这些神经化学变化，我们采用免疫细胞化学方法详细评估了芬氟拉明治疗对大鼠脑中5-HT样免疫反应性神经元的形态和密度的影响。在高剂量盐酸消旋芬氟拉明治疗（24mg/kg皮下注射，每日两次，共4天）后的12至18小时，脑内细口径5-HT样免疫反应性纤维和终末的密度出现显著的区域性降低。这种效应在大脑皮层、海马体、小脑和纹状体中尤为明显，而在隔区、蓝斑和下丘脑的降低则不太显著。另一方面，中脑核团中的5-HT样免疫反应性胞体以及脊髓中的纤维和终末在芬氟拉明治疗后未受影响。剩余的5-HT样免疫反应性纤维和终末呈现出轴突退变的形态特征（增粗、曲张肿胀和断裂）。在4天治疗方案结束两周后，5-HT样免疫染色模式与药物治疗后立即（即18小时）观察到的相似；然而，药物治疗后不久出现的严重变形的纤维和终末已不复存在。用于评估含儿茶酚胺神经元变化的酪氨酸羟化酶样免疫反应性似乎未受药物治疗的影响。这些数据表明，在大鼠中，高皮下剂量的芬氟拉明可能对某些5-HT样免疫反应性轴突和终末具有神经毒性。这些观察结果与人类继续口服较小剂量芬氟拉明进行治疗的相关性仍有待确定。
