Influence of 5-HT₁ and 5-HT₂ Receptor Antagonists on Insulin-Induced Adrenomedullary Catecholamine Release

Abstract

Previous works have indicated that insulin stress activates the serotonin (5-HT) and sympathoadrenal systems in the fasted rat. In addition, recent studies have shown that activation of either the 5-HT_1A, the 5-HT_1C or the 5-HT₂ receptor triggers adrenal catecholamine release. Then, the aim of this study was to investigate whether brain 5-HT, by means of these receptors, mediates insulin-induced adrenal catecholamine release. For that purpose, both plasma epinephrine (Epi), norepinephrine (NE) and glucose levels were measured in conscious rats bearing intracardiac catheters. The intravenous administration of insulin (1 IU/ kg) triggered hypoglycemia throughout the following 120 min in both fed and overnight fasted rats. Insulin stress elicited within 30 min a 5- and 38-fold increase in plasma Epi levels in fed and fasted rats, respectively. This change was associated with significant elevations in plasma NE levels in the fasted rats only. The intravenous administration of the mixed 5-HTIA receptor/β-adrenocep-tor blocker (–)-propranolol (5 mg/kg) to fasted rats did not modify plasma glucose and catecholamine peak responses to insulin; however, at later times, insulin triggered hypoglycemic convulsions in (–)-propranolol- but not in saline-pretreated rats. Besides, pretreatments with the 5-HT_1C5-HT₂ receptor blocker LY 53857 (0.5 mg/kg), or the 5-HT₁/5-HT₂ receptor antagonist metergoline (3 mg/kg), did not diminish plasma catecholamine responses to insulin stress. Similarly, none of these antagonists affected plasma glucose recovery. These results seem to indicate that the sympathoadrenal response to insulin administration is not mediated by 5-HT.

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes

“…Activation of a number of serotonergic receptors (5HT 1A , 5HT 1C , 5HT 2 , and 5HT 3 ) has been demonstrated to increase sympathetic nervous system outflow (5,6,38,39). Additionally, both systemic and central administration of SSRIs have specifically increased adrenal catecholamine and epinephrine release (7,8).…”

A neurochemical mechanism for hypoxia-induced anapyrexia

“…6B). Since propranolol is a mixed ␤-adrenoceptor/5-HT 1A receptor antagonist (10,24), this result would imply that a catecholamine-cAMP or a serotonin-cAMP pathway in the PO is involved in anapyrexia. However, the observation that Rp-cAMPS failed to alter the thermoregulatory response to epinephrine (Fig.…”

“…As to the pharmacology of these agents, Rp-cAMPS and Rp-cGMPS are specific membrane-permeable inhibitors of protein kinases A and G, respectively, resistant toward cyclic nucleotide phosphodiesterases (3,8). As to propranolol, it is a mixed ␤-adrenoceptor/5-HT 1A receptor antagonist (10,24). Last, L-NMMA is a nonselective NO synthase inhibitor (25), whereas sodium nitroprusside is an NO donor, i.e., it has the property of releasing NO in biological systems (25).…”

Influence of VMH fuel sensing on hypoglycemic responses

“…Interestingly, in that same study, both 6 and 20 day treatment with sertraline prevented loss of the epinephrine response in recurrently hypoglycemic animals, suggesting loss of serotonergic neurotransmission may contribute to counterregulatory failure. In contrast, another study showed that treatment with either the 5-HT1C/5-HT2 serotonin receptor blocker, LY 53857, or the 5-HT1/5-HT2 receptor antagonist, metergoline, did not diminish plasma catecholamine responses to insulin-induced hypoglycemia 60 . Differences in these findings may be due to the length of treatment and/or the site of action of the compounds used.…”