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.
Clinical Psychopharmacology Section, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland 21224, USA. mbaumann@irp.nida.nih.gov
M H
MH
Baumann
M A
MA
Ayestas
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RB
Rothman
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000008:administration & dosage* / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D011388:Prolactin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*; D013997:Time Factors
D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D011388:Prolactin; D003345:Corticosterone