Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l-fenfluramine administration to adult rats.
Fenfluramine (FEN) is a substituted amphetamine known for its anorectic effects, without the stimulatory or abuse potential associated with other amphetamine derivatives. FEN is a potent serotonin (5-HT) releaser and reuptake inhibitor and has been shown to cause depletions of 5-HT that can last days and even weeks after administration. Administration of FEN four times on a single day also causes a prolonged increase of corticosterone (CORT) that lasts approximately 72 h following the first FEN dose. This dosing regimen also produces deficits in sequential learning as measured in the Cincinnati water maze (CWM). Adrenalectomy blocks this effect but removes more than CORT. Accordingly, the purpose of this study was to determine whether inhibiting glucocorticoid production, by administration of the 11 beta-hydroxylase inhibitor metyrapone (MET), will similarly attenuate or eliminate the sequential learning deficits seen with FEN exposure. MET (50 mg/kg) injections were administered 90 min prior to and for 3 days after FEN (four doses given at 2-h intervals). Animals pretreated with MET and treated with FEN showed no sequential learning deficits when tested 1 week following FEN administration compared to FEN alone. The depletions of monoamines were similar following FEN administration, regardless of MET treatment. Taken together, this suggests that a potential mechanism for the sequential learning deficits in FEN-treated animals is a result of prolonged increases in CORT output.
Division of Developmental Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Matthew R
MR
Skelton
Tracy L
TL
Blankenmeyer
Gary A
GA
Gudelsky
Carrie A
CA
Brown-Strittholt
Charles V
CV
Vorhees
Michael T
MT
Williams
D000311:Adrenal Glands / Q000033:anatomy & histology; D000367:Age Factors; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005277:Fenfluramine; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008797:Metyrapone / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors; D013550:Swimming; D013950:Thymus Gland / Q000033:anatomy & histology
D015306:Biogenic Monoamines; D004791:Enzyme Inhibitors; D005277:Fenfluramine; D006897:Hydroxyindoleacetic Acid; D008797:Metyrapone; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors