Hyperinsulinemia of the genetically obese (fa/fa) rat is decreased by a low dose of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

doi:10.1016/0014-2999(88)90639-5

European Journal of Pharmacology

Volume 147, Issue 1, 16 February 1988, Pages 111-118

https://doi.org/10.1016/0014-2999(88)90639-5 Get rights and content

Abstract

Changes in glycemia and insulinemia were determined in conscius lean (FA/?) and obese (fa/fa) rats after acute administration of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The intravenous injection of a low dose of 8-OH-DPAT (150 μg/kg) to lean rats rapidly promoted hyperglycemia. This modification was associated with a slight increase in insulinemia. The injection of 8-OH-DPAT markedly decreased basal hyperinsulinemia in obese rats while inducing hyperglycemia. Further evidence of the strong inhibitory effect of 8-OH-DPAT on insulin release was obtained in lean and obese rats during glucose tolerance tests. Intracerebroventricular injection of 8-OH-DPAT (45 μg/animal) triggered hyperglycemia and markedly decreased insulinemia in both lean and obese rats. This hypoinsulinemic effect of 8-OH-DPAT was more pronounced in the obese than in the lean animals. Measurement of the food intake elicited by 8-OH-DPAT (500 μg/kg s.c.) showed that the hyperphagic action of the 5-HT_1A agonist was the same in FA/? and fa/fa rats. It is suggested that: (i) hyperinsulinemia of the genetically obese rat may be diminished by a low dose of 8-OH-DPAT; (ii) 5-HT_1A autoreceptor-mediated regulation of serotonergic activity is not different in lean (FA/?) and obese (fa/fa) rats; (iii) 8-OH-DPAT could be of potential therapeutic use for some aspects of the pathology of type II diabetes.

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The present study describes the role of 5-HT1A receptors in the serotonergic control of food intake in obese Zucker rats of different ages. In addition, serotonin (5-HT) and cholecystokinin (CCK) content and 5-HT turnover were determined in various brain regions. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 100 μg/kg) stimulated food intake in 3-month-old lean control rats but inhibited feeding in obese Zucker rats (300 μg/kg). This pattern remained the same in 6-month-old rats. At 10 months of age, 8-OH-DPAT lost its inhibitory activity in the obese rats but still stimulated feeding in lean controls (300 μg/kg). 5-HT levels were higher in the hypothalamus and in the frontal and parietal cortices of 3-month-old obese Zucker rats and were associated with a lower cortical turnover. In the parietal cortex and the hypothalamus of 6-month-old rats, 5-HT levels were still higher, linked with a lower hypothalamic turnover. No differences were observed in 10-month-old rats. CCK content was not different between obese Zucker rats and lean rats. The persistently different feeding responses to 8-OH-DPAT in obese Zucker rats and lean controls may be related to changes in brain 5-HT metabolism in the obese Zucker rats.
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Leptin acts as a satiety factor within the central nervous system by binding to its receptor located in the hypothalamus. A missense mutation of the leptin receptor induces hyperphagia and obesity in the obese Zucker fa/fa rat. Since the CNS is an important target of leptin action, we hypothesized that leptin gene transfer into the lateral cerebral ventricle could efficiently lead to inhibition of food intake and reduction of body weight in obese fa/fa rats as well as in lean animals. A single intracerebroventricular injection of an adenoviral vector containing a cDNA encoding leptin resulted in the expression of leptin in the ependymal cells lining the ventricle and the secretion of leptin into the cerebrospinal fluid (CSF). During the first week after injection, when high concentrations of leptin were produced in the CSF, the reducing effects of leptin on food intake and body weight were comparable in lean and in obese fa/fa rats. The subsequent decline in CSF leptin levels, that was similar in lean and obese fa/fa rats, resulted in the faster resumption of food intake and body weight gain in obese than in lean animals, confirming a reduced sensitivity to leptin in the obese group. The results of this study show that leptin gene delivery into the cerebral ventricles allows for the production of elevated leptin concentrations in CSF, and they support the hypothesis that the impaired sensitivity to leptin may be overcome in obese fa/fa rats.
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This bipartite study uses behavioral and biochemical means to explore the involvement of both pre- and post-synaptic 5-HT_1A receptors in the control of food intake and neuroendocrine regulation. In the pharmacological study, the administration of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 60 μg/kg b.wt., i.p.) to rats caused a significant increase in 2 h intake of a high carbohydrate (CARB)/sugar diet (P < 0.05) during the relatively inactive feeding period of the late light cycle. No significant change was detected in the intake of Purina laboratory chow at 2 h, or of the intake of either diet at 4 h and 24 h after 8-OH-DPAT administration. Injection of 8-OH-DPAT induced a drop in insulin levels in rats maintained on high CARB/sugar diets only (−90%; P<0.05). It also caused an increase in circulating glucose levels in both high CARB/sugar (240%; P<0.01) and chow fed (123%; P<0.05) rats; it did so more intensely in high CARB/sugar-fed rats. In the biochemical study, radioligand binding techniques were used to assess 5-HT_1A receptor density in the hypothalamus, as well as the relationship between 5-HT_1A receptors and circulating levels of insulin and glucose. Chronic and acute administration (25 mg/kg b.wt./5 injections, and 50 mg/kg b.wt., respectively, i.p.) of the potent hypoglyce mic agent tolbutamide (TOL) caused a significant increase in 5-HT_1A receptor density (+243% and +132.6%, respectively; P<0.05) in the medial hypothalamus but not in the lateral hypothalamus, as compared to vehicle-treated rats. Chronic glucose replacement therapy showed a trend towards reversing the depressed circulating glucose levels as well as the medial hypothalamic 5-HT_1A receptor density to control levels. These studies indicate that the pre-synaptic mechanism of 8-OH-DPAT-induced hyperphagia may require specific circulating levels of insulin and glucose, which are regulated via post-synaptic 5-HT_1A receptors.
Central serotoninergic system involvement in the anorexia induced by N<sup>G</sup>-nitro-L-arginine, an inhibitor of nitric oxide synthase
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The effects of N^G-nitro-L-arginine, an inhibitor of brain nitric oxide (NO) synthase, on central serotoninergic system were studied in male obese Zucker rats and in their lean age-matched controls (FA/?; FA/FA), both groups aged 14 weeks. Acute injection of N^G-nitro-L-arginine (50 mg/kg i.p.) or repeated administration of N^G-nitro-L-arginine (50 mg/kg i.p. daily, for 7 days) reduced food intake and body weight in obese rats. Acute administration of N^G-nitro-L-arginine reduced food intake in lean rats. However, lean rats showed tolerance to the N^G-nitro-L-arginine effects after repeated administration. N^G-Nitro- L-arginine administration significantly increased serotonin metabolism in the cortex, diencephalon and medulla-pons of obese Zucker rats after either acute or repeated administration of N^G-nitro-L-arginine. In contrast, N^G-nitro-L-arginine increased serotonin metabolism in lean rats only after acute administration, and the appearance of tolerance to N^G-nitro-L-arginine anorectic effects paralleled the failure of N^G-nitro-L-arginine to increase serotonin metabolism. The present data extend our previous findings indicating that N^G-nitro-L-arginine possesses anorectic activity in obese Zucker rats, and clearly suggest that the central serotoninergic system mediates the anorexia induced by inhibitors of brain NO synthase.
Effects of the selective 5-HT<inf>1A</inf> receptor antagonist WAY100135 and its enantiomers on 8-OH-DPAT-induced hyperglycaemia in conscious rats
1994, European Journal of Pharmacology
8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increases plasma glucose levels in conscious rats probably by stimulation of central 5-HT₁ receptors. We have examined the effects of WAY100135 (N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2- phenylpropanamide), a selective 5-HT_1A receptor antagonist and its enantiomers on plasma glucose levels and on the hyperglycaemia induced by 8-OH-DPAT. (R,S)-WAY100135 (minimum effective dose (MED) 3 mg/kg i.v.) and (S)-WAY100135 (MED 1 mg/kg i.v.) dose-dependently attenuated 8-OH-DPAT-induced hyperglycaemia. In contrast, (R)-WAY100135 at doses up to 3 mg/kg i.v. was unable to block hyperglycaemia induced by 8-OH-DPAT. When the antagonist were examined for intrinsic effects on plasma glucose levels only (S)-WAY100135 (3 mg/kg i.v.) caused a significant but transient hyperglycaemia (20% increase). These results are consistent with previous suggestions that (R,S)-WAY100135 and (S)-WAY100135 are selective 5-HT_1A receptor antagonist and that 8-OH-DPAT-induced hyperglycaemia is mediated by 5-HT_1A receptors. The antagonist action of WAY100135 is stereoselective, the more potent activity being observed with the (S) enantiomer.
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Hyperinsulinemia of the genetically obese (fa/fa) rat is decreased by a low dose of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

Abstract

European J. Pharmacol.

Neuropharmacology

Brain Res.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Appetite

Pharmacol. Biochem. Behav.

European J. Pharmacol.

Trends Pharmacol. Sci.

European J. Pharmacol.

Pharmacol. Biochem. Behav.

European J. Pharmacol.

Neuropharmacology

European J. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

Physiol. Behav.

European J. Pharmacol.

Hyperinsulinemia of the genetically obese (fa/fa) rat is decreased by a low dose of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)