Elsevier

Regulatory Peptides

Volume 120, Issues 1–3, 15 August 2004, Pages 107-112
Regulatory Peptides

NPY and NPY Y1 receptor effects on noradrenaline overflow from the rat brain in vitro

https://doi.org/10.1016/j.regpep.2004.02.015Get rights and content

Abstract

Neurotransmitters and neuropeptides play important roles in the regulation of various neuroendocrine functions particularly feeding. The aim of this study was to investigate whether a functional interaction occurs among neuropeptide Y (NPY) at NPY Y1 receptors and noradrenaline overflow, as this may contribute to the regulation of appetite. The release of endogenous noradrenaline and its metabolite 3,4-dihydroxyphenylglycol (DHPG) were examined from hypothalamic and medullary prisms using the technique of in vitro superfusion and high performance liquid chromatography (HPLC) with coulometric detection. Noradrenaline and DHPG overflow was investigated at rest, in response to NPY (0.1 μM) and in response to the NPY Y1 receptor agonist, [Leu31,Pro34]NPY (0.1 μM). Perfusion with NPY and [Leu31,Pro34]NPY significantly reduced noradrenaline overflow from the hypothalamus and medulla. Perfusion with NPY and [Leu31,Pro34]NPY was without significant effect on hypothalamic DHPG overflow, while medullary DHPG overflow was significantly reduced by NPY and [Leu31,Pro34]NPY. Results from this study provide evidence of NPY Y1 receptor-mediated inhibition of noradrenaline release in the hypothalamus and medulla, further illustrating a complex interaction between neurotransmitters and neuropeptides within the rat brain.

Introduction

Obesity is a major health problem in our modern society. Over the past 20 years, the prevalence of this condition has rapidly increased [1]. Obesity derives from a complex etiology, involving genetic, environmental and psychosocial factors [2]. Recent reports suggest that the central nervous system (CNS) plays an important role in the regulation of food intake [3]. Various nuclei of the hypothalamus, particularly the arcuate (ARC), paraventricular (PVN), dorsomedial (DMN) and suprachiasmatic (SCN) nuclei are involved in the regulation of energy homeostasis. The regulation of energy homeostasis involves the interaction of multiple neurotransmitters and neuropeptide systems within the brain.

A critical CNS neurotransmitter involved in the regulation of energy balance is the noradrenaline co-transmitter neuropeptide Y (NPY). NPY, a 36-amino-acid peptide, is found within the central and peripheral nervous systems in rats and humans. Within the hypothalamus, NPY stimulates feeding, reduces energy expenditure and induces weight gain (for review, see Ref. [4]). NPY Y1 and Y5 receptors play important roles in the regulation of feeding [5], [6]. Using NPY Y1 receptor deficient (Y1−/−) and NPY Y5 receptor deficient (Y5−/−) mice, Kanatani et al. [7] observed that exogenous administration of NPY significantly stimulated feeding, although a considerable reduction in food intake was reported in Y1−/− compared to Y5−/− mice. These findings suggest that the NPY Y1 receptor plays a key role in feeding regulation. NPY Y1 receptors have been observed within many regions of the brain including the PVN, median eminence, arcuate hypothalamic nucleus and nucleus tractus solitarius [8]. Few NPY Y5-like binding sites have been located within the hypothalamus [6].

Along with a role in feeding, NPY has numerous other biological functions, including facilitation of memory [9], induction of hypothermia [10] and anxiolytic potency [11]. NPY has also been located in hypothalamic and medullary regions involved in blood pressure regulation, where it is co-localised with noradrenaline. Depending on the site of NPY administration within the CNS and the presence or absence of anaesthesia, pressor and depressor results have been observed [12].

We have previously shown using the technique of in vivo microdialysis that administration of the NPY Y1 receptor agonist [Leu31,Pro34]NPY facilitated a significant reduction in basal PVN noradrenaline release [13]. Using the same in vitro superfusion technique as used here, we reported that administration of the NPY Y1 receptor antagonist GR231118 significantly abolished the reduction in noradrenaline release observed from the hypothalamus during NPY administration [14]. Prompted by these previous reports, the aim of this study was to further investigate the NPY and NPY Y1 receptor regulation of neurotransmitter release and metabolism from the rat hypothalamus and medulla in vitro. This study was designed to investigate whether there was a functional interaction among central NPY and NPY Y1 receptors in brain transmitter release, as this may contribute to the regulation of appetite.

Section snippets

Animals

Seventeen adult (322.5±16.1 g) male Sprague–Dawley rats were obtained from the Precinct Animal Centre (Baker Heart Research Institute). All procedures used in this study were performed in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. Rats received rat chow and water ad libitum and also experienced a 12-h light/dark cycle. The animal room temperature was maintained at 21±3 °C and humidity was controlled to a range of 50±10%. Animals were

Noradrenaline—hypothalamus

Basal hypothalamic noradrenaline overflow averaged 15.76±2.38 pg/mg hypothalamus/30 min, n=6. There was a slow, progressive decline in noradrenaline overflow in the control arm of the experiment (approximately 20%) over the 2 h of observation. Inclusion of NPY (0.1 μM) in the superfusate induced a delayed reduction in noradrenaline overflow to 66% of basal levels at 90 min (P<0.05; Fig. 1). Administration of the NPY Y1 receptor agonist [Leu31,Pro34]NPY in the superfusate induced a decrease in

Discussion

Multiple neurotransmitters and neuropeptides play a major role in the regulation of energy balance, feeding and body weight. Studies report an α2-noradrenergic system in the mPVN, which upon activation stimulates food intake, specifically carbohydrate intake [17], [18]. In addition, PVN noradrenaline turnover was significantly increased in food deprived α-methyl-p-tyrosine (α-MpT; a catechol synthesis inhibitor)-treated rats, compared to satiated α-MpT-treated rats [19]. Co-localisation between

Acknowledgements

We would like to thank Fiona Keurentjes and Sandra Miljavec for assisting with the animal experiments.

References (32)

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