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Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action.
Eur J Pharmacol. 2000 Mar 03; 390(3):275-85.EJ

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 environmental conditions. Moreover, there has been neglect in research on the mechanisms underlying changes in body temperature. In this study, we demonstrate that D-fenfluramine (5 and 10 mg/kg) induces a sustained decrease in body temperature in the rat under normal ambient temperatures. Pre-treatment with the selective serotonin reuptake inhibitor sertraline (5 mg/kg), the full 5-HT(1A) receptor antagonist 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinyl benzamide], WAY 100635 (0.15 mg/kg) and the 5-HT(2C) receptor antagonist 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 D120 min post-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 block the 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.

Authors+Show Affiliations

Department of Pharmacology, National University of Ireland, Galway, Ireland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10708734

Citation

Cryan, J F., et al. "Characterization of D-fenfluramine-induced Hypothermia: Evidence for Multiple Sites of Action." European Journal of Pharmacology, vol. 390, no. 3, 2000, pp. 275-85.
Cryan JF, Harkin A, Naughton M, et al. Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action. Eur J Pharmacol. 2000;390(3):275-85.
Cryan, J. F., Harkin, A., Naughton, M., Kelly, J. P., & Leonard, B. E. (2000). Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action. European Journal of Pharmacology, 390(3), 275-85.
Cryan JF, et al. Characterization of D-fenfluramine-induced Hypothermia: Evidence for Multiple Sites of Action. Eur J Pharmacol. 2000 Mar 3;390(3):275-85. PubMed PMID: 10708734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action. AU - Cryan,J F, AU - Harkin,A, AU - Naughton,M, AU - Kelly,J P, AU - Leonard,B E, PY - 2000/3/10/pubmed PY - 2000/5/16/medline PY - 2000/3/10/entrez SP - 275 EP - 85 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 390 IS - 3 N2 - 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 environmental conditions. Moreover, there has been neglect in research on the mechanisms underlying changes in body temperature. In this study, we demonstrate that D-fenfluramine (5 and 10 mg/kg) induces a sustained decrease in body temperature in the rat under normal ambient temperatures. Pre-treatment with the selective serotonin reuptake inhibitor sertraline (5 mg/kg), the full 5-HT(1A) receptor antagonist 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinyl benzamide], WAY 100635 (0.15 mg/kg) and the 5-HT(2C) receptor antagonist 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 D120 min post-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 block the 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/10708734/Characterization_of_D_fenfluramine_induced_hypothermia:_evidence_for_multiple_sites_of_action_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014299900000121 DB - PRIME DP - Unbound Medicine ER -