Administration of fenfluramine at different ambient temperatures produces different core temperature and 5-HT neurotoxicity profiles

Abstract

This study investigated the effect of two different ambient temperatures on fenfluramine-induced 5-HT neurotoxicity. Fenfluramine (FEN) (12.5 mg/kg×4; injections made hourly) or saline (SAL) was administered to rats in either a normal laboratory temperature of 24°C or a warm environment of 30°C. Animals were kept at that ambient temperature for 20 h after FEN administration. Ambient temperature was controlled to ±0.5°C and rat core temperature was continually measured using a non-invasive apparatus. FEN-treated rats at 24°C displayed a core temperature hypothermia with a peak low of 33.8°C, and this core temperature hypothermia lasted for 20 h after FEN administration. Rats treated with FEN at 30°C displayed a significant core temperature hyperthermia for 4 h after the first drug injection compared to SAL-treated groups, with a peak core temperature of 38.6°C. 2 weeks after FEN injections, brain regions were analyzed by HPLC. Both groups of FEN-treated rats showed decreases in 5-HT and 5-HIAA in the hippocampus, frontal cortex, somatosensory cortex, striatum, hypothalamus and septum. However, FEN rats treated at 30°C had significantly greater decreases (26–35%) in 5-HT compared to FEN-treated rats at 24°C in the frontal cortex, hippocampus, striatum and somatosensory cortex and significantly greater decreases (26–50%) in 5-HIAA in the frontal cortex, hippocampus and somatosensory cortex. This study indicates fenfluramine can produce neurotoxicity in rats that display either a core temperature hypothermia or hyperthermia, although hyperthermic rats have greater 5-HT and 5-HIAA depletions than the hypothermic rats.