Hyperglycemia Induced by Pharmacological Activation of Central Serotonergic Pathways Depends on the Functional Integrity of Brain CRH System and 5-HT3 Receptors

Abstract

In the present study, we investigated the effect of central serotonergic pathway activation achieved through third ventricle injections of quipazine, a serotonergic agonist, on plasma glucose levels of fasted and fed adult Wistar male rats, whose third ventricles were canulated 7 days before the experiments. Central quipazine administration induced a significant increase in plasma glucose levels in fasted animals, but was unable to modify plasma glucose concentrations in fed rats. Pretreatment with alpha-helical CRH, a CRH antagonist, significantly attenuated quipazine-induced hyperglycemia. Pretreatment with two different 5-HT3 receptor antagonists, LY-278,584 and ondansetron, was also able to produce a significant reduction in the hyperglycemic response evoked by central administration of quipazine. None of the antagonists used was capable of modifying plasma glucose concentrations when injected alone into the third ventricle. Quipazine-treated, hyperglycemic animals did not show any increase in plasma insulin levels. We conclude that acute pharmacological serotonergic stimulation by quipazine produces hyperglycemia by mechanisms that require the functional integrity of both CRH and 5-HT3 receptors, and that impairment in insulin secretion and/or activity may explain hyperglycemia induced by third ventricle injections of quipazine.

QCM-4, a serotonergic type 3 receptor modulator attenuates depression co-morbid with obesity in mice: An approach based on behavioral and biochemical investigations

“…Few clinical studies also employed 5-HT 3 receptor antagonists in several neuropsychiatric disorders (Israili, 2001;Wolf, 2000;McCann et al, 1997). Interstingly, 5-HT 3 receptor antagonists like ondansetron, LY-278584 and tropisetron have shown to regulate the plasma glucose level in various assays (Carvalho et al, 2005;Heimes et al, 2009).…”

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

“…However, it is not clear whether ondansetron alone can affect the plasma glucose levels in Mandhane et al's (2012) study. Another study showed that pretreatment with ondansetron was able to reduce the hyperglycemic response induced by central administration of quipazine; however, ondansetron injection alone into the third ventricle had no effect on plasma glucose concentrations in rodents (Carvalho et al, 2005). There have been no reports showing any effect of ondansetron on blood glucose levels in humans.…”

Effect of Tianeptine on Glucose Tolerance with Insulin Secretion in Human: Potential Anti-Diabetic Effect of the Drug

“…In addition, the fact that adrenodemedullation prevented both the glucose rise and the insulin fall, but not the glucagon rise, indicated that the effects at the beta-cell level were mediated by the adrenaline released from the adrenal glands [21,29,31,33,34,37,38].…”

“…In addition to the above and taking into account that plasma serotonin excites both alpha-cells and adrenal glands directly [21,29,[31][32][33][34], the disappearance of those hyperglycemic factors would favor the predominance of the insulinogenic effect registered in this study. This phenomenon should be associated with other findings showing that adrenalectomy is able to interfere with the glucagon induced plasma glucose rises provoked by intravenous administration of 5-HT [35].…”