This study investigated the effect of two different ambient temperatures on fenfluramine-induced 5-HT neurotoxicity. Fenfluramine (FEN) (12.5 mg/kg x 4; injections made hourly) or saline (SAL) was administered to rats in either a normal laboratory temperature of 24 degrees C or a warm environment of 30 degrees C. Animals were kept at that ambient temperature for 20 h after FEN administration. Ambient temperature was controlled to +/-0.5 degrees C and rat core temperature was continually measured using a non-invasive apparatus. FEN-treated rats at 24 degrees C displayed a core temperature hypothermia with a peak low of 33.8 degrees C, and this core temperature hypothermia lasted for 20 h after FEN administration. Rats treated with FEN at 30 degrees 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 degrees 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 degrees C had significantly greater decreases (26-35%) in 5-HT compared to FEN-treated rats at 24 degrees 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.