Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l‐fenfluramine administration to adult rats

Abstract

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.

Alterations in Body Temperature, Corticosterone, and Behavior Following the Administration of 5-Methoxy-Diisopropyltryptamine (‘Foxy’) to Adult Rats: a New Drug of Abuse

“…Interestingly, the path integration task used in this experiment, the CWM, is more sensitive at detecting detrimental effects of several substituted amphetamines in adult rats than the MWM (Able et al, 2006;Skelton et al, 2004;Williams et al, 2002) and the present results are consistent with that pattern. Comparable to the administration of fenfluramine, a potent 5-HT releaser, 5-MEO-DIPT (1) produced hypothermia during drug administration, (2) stimulated the adrenal function of the animals as demonstrated by the increased levels of CORT 3 days after drug administration and an increase in adrenal weights, and (3) disrupted CWM performance while sparing MWM performance (cf, Skelton et al, 2004;Williams et al, 2001;Williams et al, 2002). Unlike fenfluramine, 5-MEO-DIPT produced no decrease in 5-HT or 5-HIAA (Skelton et al, 2004).…”

“…All tests were performed during the light phase of the light/dark cycle. This order of testing closely follows one that we have used to assess the impact of a single day exposure to other psychostimulants in adult animals (Cohen et al, 2005;Skelton et al, 2004;Williams et al, 2002). We have previously shown that the order of the CWM and MWM does not significantly affect the outcome with these compounds (Williams et al, 2002).…”

“…In order to monitor body temperature during drug administration, the animals were injected with implantable temperature transponders (IPTT-200; BMDS, Seaford, DE), Effects of 5-MEO-DIPT MT Williams et al as described previously (Cohen et al, 2005;Skelton et al, 2004;Williams et al, 2002). Temperature transponders were implanted under isoflourane anesthesia 3 days before the experiment.…”

“…Comparable to the administration of fenfluramine, a potent 5-HT releaser, 5-MEO-DIPT (1) produced hypothermia during drug administration, (2) stimulated the adrenal function of the animals as demonstrated by the increased levels of CORT 3 days after drug administration and an increase in adrenal weights, and (3) disrupted CWM performance while sparing MWM performance (cf, Skelton et al, 2004;Williams et al, 2001;Williams et al, 2002). Unlike fenfluramine, 5-MEO-DIPT produced no decrease in 5-HT or 5-HIAA (Skelton et al, 2004). As reported recently, the lack of effect on 5-HT levels may be the result of 5-MEO-DIPT acting directly on various 5-HT receptor subtypes, although if 5-MEO-DIPT binds to the 5-HT transporter is unknown at this time.…”

“…Nonetheless, no depletions of monoamines were noted; whether this was related to drug-induced hypothermia, a protective effect with most substituted amphetamines, is not yet known and will require treating animals at different ambient temperatures to resolve. It should be noted, however, that increases in body temperature are not always required for depletions of monoamines as fenfluramine induces hypothermia and depletes serotonin without an increase in GFAP (Miller and O'Callaghan, 1995;O'Callaghan and Miller, 1994;Rowland et al, 1993;Rowland and Carlton, 1986;Skelton et al, 2004;Stewart and Slikker, 1999). The lack of depletions in monoamines and the hypothermia suggest that 5-MEO-DIPT does not induce neurotoxicity to monoaminergic neurons; however, effects on other neurotransmitters are unknown.…”