d-fenfluramine produces neuronal degeneration in localized regions of the cortex, thalamus, and cerebellum of the rat

d-Fenfluramine is a potent serotonin (5-HT) reuptake inhibitor/releaser and, until its recent recall, was prescribed as an anoretic agent. This study demonstrates that 10 mg/kg d-fenfluramine ip, when administered to rats in a warm (27 degrees C) environment, produces neuronal degeneration within select brain regions. Degeneration was detected and localized using a recently developed fluorescent marker of neuronal degeneration, Fluoro-Jade. The most extensive cortical damage was in the anterior cingulate region. In the medial thalamus, degeneration was frequently seen within the intralaminar nuclei, and somewhat less frequently observed within the paraventricular nucleus, the mediodorsal nucleus, and the gelatinosis nucleus. Cerebellar damage occurred primarily in medial Purkinje cells and occasionally in granule cells or basket cells. Degeneration was not observed in either saline-injected control animals or in rats given even higher doses of 25 mg/kg d-fenfluramine but kept in a cooler environment (23 degrees C). The degeneration was clearly most prominent in animals with body temperatures of 41 degrees to 42 degrees C, but this degeneration was not seen in animals given saline that became extremely hyperthermic in a 37 degrees C environment. Behavioral signs such as tremors, myoclonus, rigidity, and splayed legs were seen in all animals with extensive neurodegeneration. The areas damaged by d-fenfluramine, when hyperthermia occurs, could play a role in the expression of the serotonin syndrome. Elevated extracellular 5-HT levels alone are probably not sufficient for neurotoxicity, and additional factors such as hyperthermia, regional specificity of 5-HT receptor subtypes, blood flow, and/or neuronal networks may be involved.