Mechanisms involved in the hyperglycemic effect of the 5-HT1C/5-HT2 receptor agonist, DOI

doi:10.1016/0014-2999(92)90230-2

European Journal of Pharmacology

Volume 213, Issue 1, 17 March 1992, Pages 41-46

https://doi.org/10.1016/0014-2999(92)90230-2 Get rights and content

Abstract

Previous experiments have indicated that 5-HT₂ receptors and catecholaminergic systems mediate the rise in plasma glucose levels elicited by acute administration of the 5-HT_1c/5-HT₂ receptor agonists, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). On this basis, we investigated the location of these serotonin receptors and the nature of this catecholaminergic involvement. Administration of DOI (0.4 mg/kg i.v.) to conscious rats (bearing jugular catheters) elicited a rapid rise in plasma glucose which was associated with a decreased insulin response to a glucose bolus (300 mg/kg i.v.). Pretreatment with the peripherally acting 5-HT_1c/5-HT₂ receptor antagonist, BW 501C67 (0.5 mg/kg i.v. 10 min beforehand) prevented the rise in plasma glucose triggered by the peripherally acting 5-HT_1c/5-HT₂ receptor agonist, α-methyl-5-HT (0.75 mg/kg i.v.), but amplified the rise elicited by DOI. Pretreatment with chlorisondamine (1 mg/kg i.v. 10 min beforehand) or adrenalectomy 20 h beforehand prevented the DOI-induced hyperglycemia. On the other hand, pretreatment with dexamethasone (0.35 mg/kg s.c. 2 h and 20 min beforehand) did not affect the DOI-induced hyperglycemia. It is concluded that the hyperglycemic effect of DOI administration is mediated by centrally located 5-HT₂ receptors and, in turn, adrenal epinephrine release.

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In contrast to the wealth of functional data relating 5-HT circuitry and feeding, data on central serotonergic control of peripheral energy metabolism and regulation of circulating levels of the main metabolic fuels (glucose and free fatty acids) remain scarce. Pharmacological data have indicated that activation of central 5-HT1A[15] or 5-HT2 receptor subtypes [5,16] induced hyperglycemia in rat. We have failed to find evidence in the literature showing the involvement of central serotonergic circuits in the control of lipolysis in mammals.
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The somatodendritic 5-HT1A agonist 8-OH-DPAT reduces serotonergic activity and stimulates feeding in freely feeding rats. Interactions between circulating glucose and 5-HT1A receptor expression related to feeding have been described. The aim of the present microdialysis study was to (1) describe the relation between feeding and glucose in the LH, (2) to investigate if peripherally administered 8-OH-DPAT itself has an effect on extracellular glucose in the lateral hypothalamus (LH) of conscious rats. Baseline glucose concentrations were significantly different in microdialysis samples obtained from food deprived rats compared to freely feeding rats. After re-feeding, a significant rise in glucose levels by 45% was observed in the formerly food deprived rats. In freely feeding rats, 8-OH-DPAT (0.3 mg/kg, i.p.) reduced glucose level in the LH significantly. The effect of 8-OH-DPAT on brain glucose was antagonized by pre-treatment with the 5-HT1A antagonist WAY 100635 (3 mg/kg i.p.) which had no effect on its own. The data indicate, therefore, that the effect of 8-OH-DPAT on hypothalamic glucose is mediated by 5-HT1A receptors. In contrast, the same dose of 8-OH-DPAT proven effective in the brain had no effect on peripheral glucose. Only a very high dose of the 5-HT1A agonist (1.8 mg/kg i.p.) had a hyperglycaemic effect in the periphery. In conclusion, the present results show for the first time, that glucose in the lateral hypothalamus increases with a meal. The data demonstrate furthermore 8-OH-DPAT-induced changes of hypothalamic glucose level, implicating 5-HT1A receptors being involved not only in the control of hypothalamic 5-HT as shown before, but also in the control of hypothalamic glucose.

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Mechanisms involved in the hyperglycemic effect of the 5-HT1C/5-HT2 receptor agonist, DOI

Abstract

Peptides

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

J. Med. Chem.

Eur. J. Pharmacol.

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Evidence for central and peripheral serotonergic control of corticosterone secretion in the conscious rat

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Endocrinology

Mechanisms of serotonin receptor-agonist-induced activation of the hypothalamic-pituitary-adrenal axis in the rat

Endocrinology

Mechanisms involved in the hyperglycemic effect of the 5-HT_1C/5-HT₂ receptor agonist, DOI