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Titolo:
Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action
Autore:
Cryan, JF; Harkin, A; Naughton, M; Kelly, JP; Leonard, BE;
Indirizzi:
Natl Univ Ireland Univ Coll Galway, Dept Pharmacol, Galway, Ireland Natl Univ Ireland Univ Coll Galway Galway Ireland acol, Galway, Ireland
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACOLOGY
fascicolo: 3, volume: 390, anno: 2000,
pagine: 275 - 285
SICI:
0014-2999(20000303)390:3<275:CODHEF>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
MAJOR DEPRESSION; IN-VIVO; THERMOREGULATORY RESPONSES; SUBSTITUTED AMPHETAMINES; SEROTONERGIC MECHANISMS; NEUROTOXICITY PROFILES; RECEPTOR ANTAGONISTS; INDUCED HYPERTHERMIA; CORTISOL RESPONSES; DOPAMINE RELEASE;
Keywords:
D-fenfluramine; hypothermia; 5-HT1A receptor; sertraline; WAY 100635; RO 43-0440; ketanserin; parachlorophenylalanine; haloperidol; sulpiride; yohimbine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
67
Recensione:
Indirizzi per estratti:
Indirizzo: Harkin, A Natl Univ Ireland Univ Coll Galway, Dept Pharmacol, Galway, Ireland Natl Univ Ireland Univ Coll Galway Galway Ireland ay, Ireland
Citazione:
J.F. Cryan et al., "Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action", EUR J PHARM, 390(3), 2000, pp. 275-285

Abstract

The effects of D-fenfluramine on core body temperature has been largely investigated under conditions of either high or low ambient temperature, whereas little research has focused on this response under normal environmentalconditions. Moreover, there has been neglect in research on the mechanismsunderlying changes in body temperature. In this study, we demonstrate thatD-fenfluramine (5 and 10 mg/kg) induces a sustained decrease in body temperature in the rat under normal ambient temperatures. Pre-treatment with theselective serotonin reuptake inhibitor sertraline (5 mg/kg), the full 5-HT1A receptor antagonist 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinyl benzamide], WAY 100635 (0.15 mg/kg) and the 5-HT2C receptorantagonist benzofuran-2-carboxamidine, RO 43-0440 (2.5 mg/kg) blocked D-fenfluramine-induced hypothermia. Depletion of 5-hydroxytryptamine (5-HT) stores following treatment with the serotonergic neurotoxin parachlorophenylalanine reversed the initial hypothermic effects of D-fenfluramine but not the later effects, as D-fenfluramine produced a delayed hypothermia (>120 minpost-challenge) in animals pre-treated with parachlorophenylalanine. Such findings are consistent with a requirement for D-fenfluramine uptake into 5-HT neurons followed by release of 5-HT from intracellular stores and stimulation of post-synaptic 5-HT receptors to reduce body temperature. The hypothermic response to D-fenfluramine was potentiated by ketanserin pre-treatment 30 min post-challenge but then antagonized at later time intervals. Pre-treatment with the dopamine, D-2 antagonist, haloperidol (1 mg/kg) and sulpiride (30 mg/kg) had a similar effect in blocking the hypothermia as WAY 100635, suggesting a role for dopamine D-2 receptors in the response. Pre-treatment with the alpha(2)-adrenoceptor antagonist yohimbine failed to blockthe hypothermic response. These results suggest multiple sites of action mediating D-fenfluramine-induced hypothermia and may be the result of a combined effect of D-fenfluramine and its active metabolite norfenfluramine affecting not only the release of 5-HT but also stimulation of post-synaptic receptors. (C) 2000 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 01:45:11