Stimulation of either the 5-hydroxytryptamine (5-HT)(1A), the 5-HT(1C) or the 5-HT2 receptor subtype triggers adrenal catecholamine release and hyperglycemia. Nonetheless, the identity of the serotonergic receptors that mediate the effects of 5-HT release upon the sympathoadrenal system (and on plasma glucose) is still unknown. Thus, we have examined the effects of the 5-HT uptake inhibitor and releaser d-fenfluramine (d-Fen) on plasma epinephrine (EPI), norepinephrine (NE) and glucose levels in conscious rats. Acute administration of d-Fen (1-8 mg/kg i.v.) promoted early increases in plasma EPI and glucose levels, whereas increases in plasma NE levels were less marked. The effects of a 4-mg/kg dose of d-Fen were then evaluated. Prior adrenalectomy prevented d-Fen-induced hyperglycemia but not d-Fen- induced increases in plasma NE levels. Pretreatment (15 min beforehand) with either the 5-HT(1C)/5-HT2 receptor antagonist LY 53857 (0.3 mg/kg i.v.) or the 5-HT2 receptor/alpha-1 adrenoceptor antagonist ketanserin (0.3 mg/kg i.v.) markedly diminished the EPI-releasing effect of d-Fen. Pretreatment with the 5-HT(1C) receptor agonist/5-HT2 receptor antagonist m- chlorophenylpiperazine (1 mg/kg i.v.) tended to decrease the EPI-releasing effect of d-Fen, whereas that with the peripheral 5-HT(1C)/5-HT2 receptor antagonist BW 501C67 (0.5 mg/kg i.v.) did not alter the EPI-releasing effect of d-Fen. In addition, pretreatment with either LY 53857 or ketanserin prevented the hyperglycemic effect of d-Fen. In another study, administration of the 5-HT(1C)/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane (0.5-1 mg/kg i.v.) increased plasma EPI levels but not NE levels, whereas neither the peripheral 5-HT(1C)/5-HT2 receptor agonist α- methyl-5-HT (0.5 mg/kg i.v.) nor m-chlorophenylpiperazine (0.5-1 mg/kg i.v.) affected plasma catecholamines. Pretreatment (15 min beforehand) with either the 5-HT(1A,B) receptor/beta adrenoceptor antagonist (-)-propranolol (5 mg/kg i.v.), the alpha-1 adrenoceptor antagonist prazosin (0.3 mg/kg i.v.) or the alpha-2 adrenoceptor antagonist idazoxan (1 mg/kg i.v.) did not significantly affect d-Fen-induced EPI release. Lastly, pretreatment with (-)-propranolol and idazoxan, respectively, reduced and amplified the effect of d-Fen on plasma NE levels. These results indicate that high doses of d-Fen trigger adrenal EPI release and hyperglycemia, mainly through 5-HT release and, in turn, stimulation of central 5-HT2 receptors. In addition, these data suggest that 5-HT2 receptor desensitization could be involved in plasma catecholamine and blood pressure decreases after repeated d-Fen treatment.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1992|
ASJC Scopus subject areas
- Molecular Medicine