Clinical Psychopharmacology Section, Division of Intramural Research (DIR), National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), P.O. Box 5180, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA
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.
