Immunohistochemical and Autoradiographic Investigations of High-Dose Fenfluramine Treatment on Monoamine Neurons in Rat Brain

Abstract

Immunohistochemistry and in vitro receptor autoradiography were used to examine effects of high-dose fenfluramine treatment (24 mg/kg, s.c., b.i.d., 4 days) on serotonergic and catecholaminergic neurons in rat brain. At 18 h following fenfluramine treatment, striking decreases were observed in the density of fine-caliber serotonin (5HT)-like immunostained axons in cerebral cortex, hippocampus, cerebellum and striatum when compared to saline-administered controls; lesser decreases were noted in septum, locus coeruleus and hypothalamus. Some persisting 5HT-like immunoreactive fibers displayed morphology reminiscent of degenerating axons (thickening, swollen varicosities and fragmentation). Of note, 5HT-like- immunoreactive cell bodies in midbrain raphe nuclei and fibers in spinal cord appeared unaffected by the treatment. Autoradiographic studies revealed that fenfluramine treatment reduced the density of 3H-paroxetine-labeled 5HT uptake sites, another index of structural integrity of 5HT axons, in parallel with decreases in density of 5HT-like immunostaining. Tyrosine hydroxylase-like immunoreactivity, used to assess effects of fenfluramine treatment on catecholaminergic axons, was unaffected. These data suggest that, in rats, high s.c. doses of fenfluramine may have neurotoxic-like effects on some 5HT-like immunoreactive axons and terminals. The relevance of these observations to the continued therapeutic use, in humans, of smaller oral doses of fenfluramine remains to be determined.