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Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release in the hypothalamus

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Abstract

Ghrelin and amylin are gut-derived hormones that stimulate and inhibit food intake, respectively. Feeding is modulated by aminergic neurotransmitters in the hypothalamus. We have evaluated the effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release from rat hypothalamic synaptosomes. We found that ghrelin did not modify dopamine or norepinephrine release, but inhibited serotonin release. On the other hand, amylin inhibited dopamine release, without affecting norepinephrine or serotonin. We conclude that the appetite-stimulating activity of ghrelin could be mediated by inhibited serotonin release, while the anorectic effects of amylin could involve inhibited release of dopamine in the hypothalamus.

Introduction

The appetite regulatory network is modulated at the hypothalamic level by the interaction of hormonal and neuronal signaling (Kalra et al., 1999). Ghrelin is a 28-amino acid peptide hormone, which has been isolated from the rat stomach as the endogenous ligand for the growth hormone (GH) secretagogue receptor (Kojima et al., 1999), but it is also produced in the hypothalamus. Besides its GH-releasing activity, ghrelin stimulates food intake and increases fat stores, either when administered peripherally or intracerebroventricularly, at dosages in the nanomolar or picomolar range, respectively (Tschop et al., 2000). Food intake is markedly stimulated after microinjection into the arcuate nucleus of the hypothalamus, which is potentially accessible to the circulation (Wren et al., 2001). The orexigenic activity of ghrelin is partially mediated by agouti-related peptide (AGRP) and neuropeptide Y (Nakazato et al., 2001), both of which are well known appetite-stimulating signals. Ghrelin can also antagonize the anorectic effect of leptin through the activation of the hypothalamic neuropeptide Y/Y1 receptor pathway (Shintani et al., 2001).

Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by pancreatic β-cells following meals, playing a role in glucose homeostasis (Ludvik et al., 1997). Peripheral amylin is able to cross the blood–brain barrier Banks et al., 1995, Banks and Kastin, 1998, but amylin-immunoreactive neurons are also present in the hypothalamus (D'Este et al., 2001). With respect to feeding behavior, amylin plays a role opposite to ghrelin, in inhibiting food intake following both systemic (10 nmol/kg) and intracerebroventricular administration (100 pmol) Chance et al., 1991, Rushing et al., 2000.

Aminergic neurotransmitters have long been implicated in feeding control at the hypothalamic level (Kalra et al., 1999), and we have previously found that peptide hormones or neuropeptides such as leptin, thyrotropin-releasing hormone (TRH), cocaine- and amphetamine-regulated transcript (CART) peptide, and the orexins A and B differently modulate hypothalamic dopamine, norepinephrine and serotonin release, which could partially explain their appetite regulatory activity Brunetti et al., 1999, Brunetti et al., 2000, Orlando et al., 2001.

In order to further investigate the endocrine link between the digestive tract and the central nervous system, particularly with regard to the feeding regulatory mechanisms, in the present study, we have evaluated the effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release from rat hypothalamic neuronal terminals (synaptosomes) in vitro.

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Materials and methods

As previously described (Brunetti et al., 1999), hypothalamic synaptosomes were prepared from male Wistar rats (200–250 g), loaded with either [3H]dopamine, [3H]norepinephrine or [3H]serotonin, perfused in water-jacketed superfusion chambers with Krebs–Ringer buffer (0.6 ml/min), and perfusate was collected (1 min fractions for serotonin, and 2 min fractions for dopamine and norepinephrine release) to detect released [3H] by liquid scintillation scanning. The European Community guidelines for

Results

Ghrelin, in the dose range 1–100 nM, did not affect basal amine release. Means±S.E.M. of the percentage of [3H]amine recovered in the stimulus and return to basal fractions with respect to total loaded [3H] were as follows: [3H]dopamine: control, 1.63±0.02; 1 nM, 1.59±0.02; 10 nM, 1.69±0.04; 100 nM, 1.68±0.06; [3H]norepinephrine: control, 1.28±0.02; 1 nM, 1.28±0.02; 10 nM, 1.29±0.03; 100 nM, 1.32±0.05; [3H]serotonin: control, 1.87±0.02; 1 nM, 1.91±0.04; 10 nM, 1.81±0.04; 100 nM, 1.85±0.03.

On

Discussion

The aminergic system plays a still unsettled role in the fine-tuning of feeding behavior at the hypothalamic level. On one side, dopamine administration into the hypothalamus inhibits food intake (Gillard et al., 1993), and the well-established anorectic effects of amphetamines could be explained by dopamine re-uptake inhibition in the lateral hypothalamus (Samanin and Garattini, 1993). On the other hand, dopamine injection into the lateral hypothalamus stimulates feeding behavior and obese

Acknowledgements

This work was supported by a MURST grant. We are grateful to Dr. M. Amitrano for her skilful technical assistance and Dr. A.F. Parlow, National Hormone and Pituitary Program, USA, for generously providing recombinant human leptin.

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