Mechanisms involved in the hyperglycemic effect of the 5-HT1C/5-HT2 receptor agonist, DOI.
Previous experiments have indicated that 5-HT2 receptors and catecholaminergic systems mediate the rise in plasma glucose levels elicited by acute administration of the 5-HT1c/5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). On this basis, we investigated the location of these serotonin receptors and the nature of this catecholaminergic involvement. Administration of DOI (0.4 mg/kg i.v.) to conscious rats (bearing jugular catheters) elicited a rapid rise in plasma glucose which was associated with a decreased insulin response to a glucose bolus (300 mg/kg i.v.). Pretreatment with the peripherally acting 5-HT1c/5-HT2 receptor antagonist, BW 501C67 (0.5 mg/kg i.v. 10 min beforehand) prevented the rise in plasma glucose triggered by the peripherally acting 5-HT1c/5-HT2 receptor agonist, alpha-methyl-5-HT (0.75 mg/kg i.v.), but amplified the rise elicited by DOI. Pretreatment with chlorisondamine (1 mg/kg i.v. 10 min beforehand) or adrenalectomy 20 h beforehand prevented the DOI-induced hyperglycemia. On the other hand, pretreatment with dexamethasone (0.35 mg/kg s.c. 2 h and 20 min beforehand) did not affect the DOI-induced hyperglycemia. It is concluded that the hyperglycemic effect of DOI administration is mediated by centrally located 5-HT2 receptors and, in turn, adrenal epinephrine release.
Baudrie
V
V
Laboratoire de Pharmacologie, CNRS, CHU Necker, Paris, France.
Chaouloff
F
F
D000315:Adrenalectomy; D000578:Amidines / Q000494:pharmacology; D000662:Amphetamines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D002714:Chlorisondamine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism*; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology
D000578:Amidines; D000662:Amphetamines; D001786:Blood Glucose; D007328:Insulin; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C029751:BW 501C; D003907:Dexamethasone; D002714:Chlorisondamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine