Effects of the 5-HT 1C/5-HT 2 receptor agonists DOI and α-methyl-5-HT on plasma glucose and insulin levels in the rat

Abstract

Administration of the 5-HT 1C/5-HT 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 0.125–2.0 mg/kg i.v.) triggered dose-dependent increases in plasma insulin levels remained unchanged. Pretreatment with the 5-HT 1C/5-HT 2 receptor antagonists LY 53857, risanserin, or the mixed 5-HT 2/ α 1-adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT 1C receptor agonists/5-HT 2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-(trifluoromethyl) phenyl)piperazine (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The α 2-adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, whilst the α 1-adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT 1C/5-HT 2 receptor agonist α-methyl-5-HT (0.5–1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished α-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT 2 receptors, but not 5-HT 1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT 2 receptors may affect glycemia.