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

Yamada, Jun; Sugimoto, Yukihiko; Yoshikawa, Tomohiro; Kimura, Ikuko; Horisaka, Kazuyoshi

doi:10.1016/0024-3205(95)02010-g

Cited by 34 publications

(21 citation statements)

References 18 publications

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“…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]. Finally, the fact that methysergide, a 5-HT antagonist, can prevent the glucagon effects, affords additional support to the postulation that serotonin was the responsible factor for the above phenomenon by acting at the islet cells directly [28,36].…”

Section: Peripheral Mechanismssupporting

confidence: 54%

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

Lechín¹,

Dijs²,

Maldonado³

et al. 2009

TONEUROEJ

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Due to the fact that drugs which interfere with the serotonin (5-HT) uptake (doxepin, sertraline, fluvoxamine and fluoxetine), were able to minimize the insulin release from islet beta-cells and counteract hypoglycemia, we investigated the effects of tianeptine, a drug which enhances 5-HT uptake during the oral glucose tolerance test. We found that the drug triggered significant and sustained insulin rises which were opposite to the plasma glucose decreases. The fact that significant noradrenaline/adrenaline (NA/Ad) plasma ratio paralleled insulin rises throughout the test is consistent with the excitatory role played by the peripheral neural sympathetic activity. Additionally, the positive correlations registered between NA versus DA (dopamine) plasma levels indicate that the latter arose from sympathetic nerves rather than the adrenal glands. Furthermore, the significant reductions of both platelet and plasma 5-HT registered throughout the OGTT plus tianeptine test support the postulation that reduction of the parasympathetic drives is occurring. This parasympathetic drive is responsible for the secretion of 5-HT from the enterochromaffin cells. Finally, considering that circulating 5-HT excites alpha-cells and modulates beta-cells, it is possible to infer that minimization of this factor contributed to the insulinogenic effect displayed by the association of this drug to an oral glucose load. We also discussed the peripheral and central nervous system mechanisms responsible for the insulinogenic effect registered throughout the test.

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Section: Peripheral Mechanismssupporting

confidence: 54%

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

Lechín¹,

Dijs²,

Maldonado³

et al. 2009

TONEUROEJ

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“…19) As shown in results, food intake gradually increased after the injection of 2-DG for 2 h. We previously found that 5-HT i.p. elevated plasma glucose levels and its effects abolished within 2 h. 16) Thus, we examined effects of 5-HT on 2-DG-induced hyperphagia for 2 h.…”

Section: Discussionmentioning

confidence: 99%

“…The peripheral 5-HT receptor participates in glucose regulation. [14][15][16][17] We reported that peripheral 5-HT elicits hyperglycemia in rats.16) Thus, 5-HT may affect food intake in 2-DG-treated rats through modifying glucose levels. We also examined effects of 5-HT on blood glucose levels in 2-DG-treated rats.…”

mentioning

confidence: 96%

Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Sugimoto

Yoshikawa

Yamada

2002

Biological & Pharmaceutical Bulletin

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Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and regulates several physiological functions. It is well established that 5-HT is an important factor controlling food intake and that 5-HT depresses food intake in animals and humans mediated by 5-HT receptors.1-3) Activation of central 5-HT 1B , 5-HT 2A and 5-HT 2C receptors induces anorexia in rodents based on numerous results using 5-HT receptor agonists and antagonists.1,2,4-7) Direct administration of 5-HT into the brain also induces hypophagia in rodents and its effects may be elicited by these 5-HT receptors. 3)Peripherally administered 5-HT induces anorexia and this effect may be associated with peripheral 5-HT 2 receptors, since it was antagonized by the peripheral 5-HT 2 receptor antagonist xylamidine. [8][9][10] We previously reported that the peripheral 5-HT 2 receptor agonist a-methyl-5-HT, reduces food intake in fasted rats and that it is mediated by the peripheral 5-HT 2A receptor.11) We also found that the peripheral 5-HT 3 receptor agonist 2-methyl-5-hydroxytryptamine did not affect food intake in rats, which implying that the peripheral 5-HT 3 receptor is not associated with food intake. 11)It is known that 2-deoxy-D-glucose(2-DG) prevents utilization of intracellular glucose and elicits neuroglucopenia, leading to hyperphagia. 12,13) To date, 2-DG-induced feeding serves as an animal model of hyperphagia. However, the effects of 5-HT itself on 2-DG-induced hyperphagia remain unclear. In the present study, therefore, we investigated the effects of peripheral administration of 5-HT on hyperphagia elicited by 2-DG in rats.Since 2-DG induces glucoprivation by inhibition of glucose utilization of cells, it elevates plasma glucose levels to compensate it. 12,13) 2-DG-induced hyperphagia is elicited in response to low glucose levels in the brain. It suggests that facilitation of hyperglycemia may improve shortage of glucose in the brain by increasing glucose uptake to cells, which may lead to inhibition of hyperphagia. The peripheral 5-HT receptor participates in glucose regulation. [14][15][16][17] We reported that peripheral 5-HT elicits hyperglycemia in rats.16) Thus, 5-HT may affect food intake in 2-DG-treated rats through modifying glucose levels. We also examined effects of 5-HT on blood glucose levels in 2-DG-treated rats. MATERIALS AND METHODS AnimalsMale Sprague-Dawley rats (200-240 g) were obtained from SLC Japan. They were housed in individual cages and maintained under a controlled 12 h : 12 h light/dark cycle ( lights on at 07:00 h), with room temperature at 23Ϯ 1°C and humidity at 55Ϯ5% for at least 7 d prior to experiments. Rats were given free access to food and water.Drugs and Treatment 2-DG and 5-HT creatinine sulfate were purchased from Wako Pure Chemical Co. (Japan), Merck (Germany), respectively. Ketanserin tartrate were obtained from Research Biochemicals Inc. (U.S.A.). 2-DG, 5-HT and ketanserin were dissolved in saline. All drugs were injected i.p. 2-DG and 5-HT were injected i.p. simultaneously at opposite sites. Ket...

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“…In addition to its role as a neurotransmitter, 5-HT has a range of functions that include control of vascular tone, exocrine secretion by the pancreas [4], liver regeneration [5] and glucose homeostasis [6][7][8]. Studies in vivo have shown either hypoglycaemia [6,7] or hyperglycaemia [8] after administration of 5-HT.…”

mentioning

confidence: 99%

“…Studies in vivo have shown either hypoglycaemia [6,7] or hyperglycaemia [8] after administration of 5-HT. The latter is attributed to release of epinephrine from the adrenal glands or to vasoconstrictor effects.…”

mentioning

confidence: 99%

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

2007

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Aims/hypothesis Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT. Materials and methods Rat hepatocytes were studied in short-term primary culture. Results Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by α-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. α-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by α-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of α-methyl-5-HT on phosphorylase inactivation. Conclusions/interpretation This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

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

Cited by 34 publications

References 18 publications

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

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

Effects of Peripheral Administration of 5-Hydroxytryptamine (5-HT) on 2-Deoxy-D-glucose-Induced Hyperphagia in Rats.

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

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