Kazuyoshi Horisaka

The involvement of the peripheral 5-HT2A receptor in peripherally administered serotonin-induced hyperglycemia in rats

The mechanism of the hyperglycemic response to intraperitoneally administered serotonin (5-HT) was studied in rats. 5-HT i.p.-induced hyperglycemia was strongly antagonized by the 5-HT2A receptor antagonist ketanserin. 5-HT did not affect the serum insulin levels and increased plasma glucagon levels only at the high dose of 10 mg/kg. 5-HT dose-dependently induced a remarkable increase in plasma adrenaline levels and these effects were antagonized by ketanserin. 5-HT-induced hyperglycemia was abolished by adrenodemedullation. These results suggest that the hyperglycemic effects of 5-HT are closely related to the release of adrenaline from the adrenal gland, mediated by 5-HT2A receptors.

Effects of the 5-HT2C/2B receptor agonist 1-(3-chlorophenyl) piperazine on plasma glucose levels of rats.

Acute administration of the 5-HT2C/2B receptor agonist 1-(3-chlorophenyl)piperazine (mCPP, 5-10 mg/kg i.p.) induced hyperglycemia in rats. These changes were diminished in a dose-dependent manner by the 5-HT1/5-HT2 receptor antagonist methysergide and the 5-HT2A/2B/2C receptor antagonist ritanserin. In addition, mCPP-induced hyperglycemia was dose dependently diminished by the ganglionic blocker hexamethonium and was prevented by prior adrenodemedullation. Neither the 5-HT2A receptor antagonist ketanserin nor the 5-HT3/5-HT4 receptor antagonist (3-alpha-tropanyl)-1 H-indole-3-carboxylic acid ester (ICS 205-930) proved effective against mCPP-induced hyperglycemia. Lastly, administration of the 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI) increased plasma glucose levels through ketanserin- and ritanserin-sensitive processes. Our results suggest that hyperglycemia elicited by mCPP is mediated by 5-HT2C and/or 2B receptors, and in turn adrenomedullary catecholamine release, whereas that elicited by DOI involves 5-HT2A receptors.

Effects of peripheral 5-HT2 and 5-HT3 receptor agonists on food intake in food-deprived and 2-deoxy-D-glucose-treated rats.

Peripherally administered, the 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT), significantly suppressed the food intake of food-deprived rats. alpha-Methyl-5-HT also inhibited 2-deoxy-D-glucose-induced hyperphagia in rats. The alpha-methyl-5-HT-induced hypophagia was antagonized by the 5-HT2A receptor antagonist, ketanserin. The alpha-methyl-5-HT-induced decrease in food intake of food-deprived rats was not inhibited by prior adrenodemedullation. The peripheral 5-HT3 receptor agonist, 2-methyl-5-HT, did not affect food intake in food-deprived or 2-deoxy-D-glucose-treated rats. These results suggest that the peripheral 5-HT2A receptor may participate in the regulation of food intake and that its hypophagic effects are not associated with its adrenaline-releasing effects from the adrenal gland. Lastly, the peripheral 5-HT3 receptor did not participate in feeding control.

Effects of a nitric oxide synthase inhibitor on 5-HT1A receptor agonist 8-OH-DPAT-induced hyperphagia in rats

We investigated nitric oxide (NO) involvement in the hyperphagia induced by the 5-HT1A receptor agonist 8-hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT). A NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), dose dependently inhibited 8-OH-DPAT-induced eating in freely feeding rats. However, the inactive isomer D-NAME was without effect. The inhibitory effects of L-NAME on 8-OH-DPAT-induced hyperphagia were reversed by simultaneous administration of L-arginine. These results suggest that NO participates in the 8-OH-DPAT-induced hyperphagia which is elicited by activation of the 5-HT1A receptor.

Hyperglycemia induced by the 5-HT receptor agonist, 5-methoxytryptamine, in rats: involvement of the peripheral 5-HT2A receptor.

The effects of the 5-HT receptor agonist, 5-methoxytryptamine, on plasma glucose levels were investigated in rats. 5-Methoxytryptamine induced a significant hyperglycemia above the dosage of 1 mg/kg. 5-Methoxytryptamine-induced hyperglycemia was antagonized by pretreatment with the 5-HT1 and 5-HT2 receptor antagonist, methysergide, or the 5-HT2A receptor antagonist, ketanserin, whereas the 5-HT3 and 5-HT4 receptor antagonist, tropisetron, and the 5-HT4 receptor antagonist, SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester), showed no effect. In addition, the peripheral 5-HT2 receptor antagonist, xylamidine, reduced 5-methoxytryptamine-induced hyperglycemia. These results suggest that 5-methoxytryptamine-induced hyperglycemia is mediated by the peripheral 5-HT2A receptor, although it has a high affinity for the 5-HT4 receptor. Adrenodemedullation abolished the 5-methoxytryptamine-induced hyperglycemia. 5-Methoxytryptamine did not affect the blood levels of the pancreatic hormones, insulin and glucagon. The hyperglycemia induced by 5-methoxytryptamine was not affected by pretreatment with dexamethasone which inhibits corticosterone release. These results indicate that 5-methoxytryptamine-induced hyperglycemia is elicited by a facilitated adrenaline release from the adrenal gland. Therefore, it is suggested that the 5-HT2A receptor may be partly involved in the pharmacological effects induced by the 5-HT4 receptor agonist, 5-methoxytryptamine.

The Effects of Peripheral Serotonin2 Receptor Agonist on Food Intake of Rats

It has been reported that the serotonin2 (5-HT2) receptor is involved in several physiological effects of 5-HT such as platelet aggregation and hypertension (Fozard, 1989). It has been suggested that 5-HT participates in the regulation of food intake and that activation of the serotonergic system decreases food intake in rats (Blundell, 1984; Curzon, 1990). It has been reported that the central 5-HT2A/2C receptor agonist DOI or 5-HT2C receptor agonist mCPP induces a decrease in food intake in rats and that these receptors may be mediated by the central effects of 5-HT on food intake (Aulakh et al., 1992; Schechter and Simansky, 1988; Kennet and Curzon, 1991). However, the involvement of the peripheral 5-HT2 receptor in food intake is not well established and the effects of the peripheral 5-HT2 receptor agonist is not yet clear. Therefore, in this study, we investigated the effects of the peripheral 5-HT2 receptor agonist α-methyl-5-HT on the food intake of rats.

Effects of adrenodemedullation and adrenalectomy on the 5-HT2 receptor agonists DOI- and mCPP-induced hypophagia in rats

Effects of adrenodemedullation and adrenalectomy on the serotonin2 (5-HT2) receptor agonists-induced hypophagia were investigated. Hypophagia induced by both the 5-HT2A/2C, receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2C-receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) were not affected by adrenodemedullation. In adrenalectomized rats. DOI did not induce hypophagia, while mCPP elicited apparent effects. These results suggest that neither DOI- nor mCPP-induced hypophagia was not associated with adrenaline release from the adrenal medulla. Moreover, our results suggest that DOI-induced hypophagia is involved in corticosterone-sensitive feeding, although other mechanisms which are not related to corticosterone are involved in mCPP-induced anorexia.

The Involvement of Serotonin the Catecholamine Release From the Adrenal Medulla

Previous studies have suggested that central serotonin (5-HT) receptors are involved in adrenaline release from the adrenal gland. The central 5-HT receptor agonists including the 5-HT1A agonist 8-OH-DPAT, the 5-HT2 receptor agonist DOI and the 5-HT2C receptor agonist mCPP can elevate plasma adrenaline levels in rats (Bagdy et al., 1989; Chaouloff et al., 1990). These effects are thought to be mediated by facilitation of centrally located receptors. We previously found that peripherally administered 5-HT induces hyperglycemia in rats and that these hyperglycemic effects were abolished by adrenodemedullation(Yamada et al., 1995). It suggests that 5—HT—induced hyperglycemia is related to adrenaline release from the adrenal gland and the peripheral 5-HT receptor may also be connected to adrenaline release. However, the peripheral effects of 5—HT on catecholamine release are not yet clear. In this study, we investigated the effects of peripherally administered 5-HT on the plasma adrenaline levels in rats. Furthermore, we examined the effects of 5-HT on catecholamine release in cultured bovine adrenal chromaffin cells.