In vivo correlates of central serotonin function after high-dose fenfluramine administration

High doses of fenfluramine (FEN) are known to deplete central serotonin (5-HT) in animals, but functional impairments associated with such 5-HT depletion have been difficult to identify. In the present work, we examined neuroendocrine responsiveness in rats exposed to repeated high-dose FEN treatment. Male rats fitted with indwelling catheters received FEN (20 mg/kg, subcutaneously, twice a day) or saline for 4 days. At 1 and 2 weeks after treatment, rats were challenged with intravenous FEN (1.5 & 3 mg/kg) or saline. Repeated blood samples were drawn, and plasma was assayed for prolactin and corticosterone by radioimmunoassay. Acute FEN challenge caused dose-dependent elevations of plasma prolactin and corticosterone in all rats. However, the FEN-induced hormone responses were significantly blunted (p < 0.01) in rats previously exposed to FEN. The repeated FEN dosing regimen dramatically reduced (> 50%) postmortem 5-HT levels in the mediobasal hypothalamus, basolateral amygdala, and hippocampus, while the lateral hypothalamus was unaffected. These data suggest that high-dose FEN causes alterations in central 5-HT systems involved with pituitary hormone secretion. The relevance of the present data to the clinical use of FEN is unclear. Because the neuroendocrine challenge paradigm is able to identify functional 5-HT deficits in rats, we propose that similar experiments should be performed in humans. Neuroendocrine challenge tests represent a reliable method to test the existence of FEN-induced neurotoxicity in human patients undergoing long-term FEN treatment.