NPY and NPY Y1 receptor effects on noradrenaline overflow from the rat brain in vitro
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.
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2016, Experimental NeurologyCitation Excerpt :For example, fasting prior to fear conditioning impairs fear acquisition, but fasting prior to extinction improves extinction learning (Verma et al., 2015). NPY may play a critical role as it modulates both NE and CRH activity, resulting in the attenuation of anxiety-like behavior and HPA axis activity (Hastings et al., 2004; Rasmusson et al., 2000; Sah and Geracioti, 2013). In a fear-conditioning paradigm, NPY reduces or inhibits the acquisition of contextual fear memories (Karlsson et al., 2005; Lach and de Lima, 2013) and also increases the extinction of conditioned fear in rats (Gutman et al., 2008).
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2015, Neurobiology of StressCitation Excerpt :One example occurs in the LC, where CRF serves as an excitatory neurotransmitter (Valentino et al., 1983) and NPY decreases the LC-noradrenergic neuronal firing (Illes et al., 1993). Consequently, central administration of NPY decreases NE overflow by acting on Y1 receptors (Hastings et al., 2004). Because evidence of elevated LC activity has been linked to depression and PTSD (Wong et al., 2000; Geracioti et al., 2001) this NPY-induced brake on LC over activation may therefore promote stress resilience.
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2014, Progress in NeurobiologyCitation Excerpt :A fine tuning neuromodulator has the capacity to exert subtle influence on synapse activity by changing receptor activation of other neurotransmitters or neuromodulators as well as its own receptors. NPY co-localizes with other neurotransmitters in different areas of the CNS (Allen et al., 1983; Hendry et al., 1984; McDonald, 1996; Silva et al., 2005) and modulates the release of several neurotransmitters (Silva et al., 2005), inhibiting the release of glutamate, aspartate, growth hormone, epinephrine and acetylcholine (Bitran et al., 1999; Bleakman et al., 1992; Greber et al., 1994; Gu et al., 1983; Hastings et al., 2004; Martire et al., 1995; Potter, 1987; Rettori et al., 1990b; Rodi et al., 2003; Schwertfeger et al., 2004; Silva et al., 2001, 2003; Tsuda et al., 1995), and enhancing the release of somatostatin and dopamine and the production of nitric oxide (Ault and Werling, 1999; Bitran et al., 1999; Rettori et al., 1990a). Therefore, NPY may play a fine-tuning modulator in the nervous system (Grandt et al., 1996; Magni, 2003; Mazzocchi et al., 1996; Prod’homme et al., 2006).
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2013, Neurobiology of Learning and MemoryCitation Excerpt :Central NPY has its effect mediated by G-protein-coupled downstream signaling through four NPY receptors: NPYY1, Y2, Y4 and Y5, with the Y1 subtype being suggested as the main candidate for attenuating the consequences of stress exposure, acting as a buffer by potentiating components of the resilience system in the CNS (Cohen et al., 2012; Gutman et al., 2008; Primeaux, Wilson, Cusick, York, & Wilson, 2005; Sajdyk, Vandergriff, & Gehlert, 1999). It is suggested that NPY works controlling the activity of stress transmitters such as norepinephrine (NE) and corticotrophin-releasing hormone (CRH), toning down central activity in brain areas related to stress response (Hastings, Morris, Lambert, Lambert, & Esler, 2004; Pavia, Hastings, & Morris, 1995; Rasmusson et al., 2000; Sah & Geracioti, 2012). In one of the first works analyzing the effect of NPY on fear responses, Broqua, Wettstein, Rocher, Gauthier-Martin, and Junien (1995) found that NPY (0.23–2.3 nmol, i.c.v.) and Y1 agonists dose-dependently inhibited the acquisition of fear-potentiated startle (FPS) in rats.
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