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The Role of Dopaminergic and Cannabinoidergic Receptors on Ghrelin-Induced Hypophagia in 5Days Old Broiler Chicken

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The Role of Dopaminergic and Cannabinoidergic Receptors on Ghrelin-Induced Hypophagia in 5Days Old Broiler Chicken Archives of Razi Institute, Vol. 76, No. 3 (2021) ???-??? Copyright © 2021 by Razi Vaccine & Serum Research 10.22092/ari.2020.351261.1514 The role of dopaminergic and cannabinoidergic receptors on ghrelin-induced hypophagia in 5days old broiler chicken Farrokhi, R. 1, Babapour, V. 2 *, Zendehdel, M. 2, Asghari, A. 3, Gilanpour, H. 1 1. Department of Basic Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran 2. Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran 3. Department of Clinical Science, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran Email: [email protected] Abstract The present study aimed to identify the role of dopaminergic (DAergic) and cannabinoidergic (CBergic) systems in the ghrelin-induced hypophagia among meat-type chickens. In the first experiment, intracerebroventricular (ICV) injection was applied to birds with control solution, D1 receptor antagonist (5nmol), ghrelin (6nmol), and D1 receptor antagonist plus ghrelin. The second to sixth experiments were similar to the first one, with the difference that D2 receptor antagonist (5nmol), D3 receptor antagonist (6.4nmol), D4 receptor antagonist (6nmol), the precursor of dopamine (125nmol), and 6-hydroxy dopamine (150nmol) instead of D1 antagonist were injected into the broiler chickens. In experiment 7, control solution and different levels of ghrelin antagonists (5, 10, and 20nmol) were injected. In experiment 8, the chickens were ICV injected with control solution, ghrelin antagonist (10nmol), dopamine (40nmol) and ghrelin antagonist plus dopamine . In experiments 9 and 10, CB 1 and CB 2 receptors antagonist ( 6.25µg and 5µg) were co-injected with ghrelin (6nmol), respectively, measuring the food intake for 120 minutes after the injection. It was observed that ghrelin ICV injection considerably reduced, food intake, whereas ghrelin antagonist increased food intake, depending on the dose (P <0.05). In addition, ghrelin-induced hypophagia was significantly attenuated by D1 receptor antagonist and 6-hydroxy dopamine (P<0.05), while the dopamine precursor considerably elevated the ghrelin-induced food intake (P <0.05). The dopamine- induced feeding behavior was diminished by the co-administration of [D-Lys-3]-GHRP-6 (10 nmol) + dopamine (40 nmol) (P <0.05). In addition, CB 1 receptor antagonists enhanced the ghrelin influence on food intake (P <0.05). The results implied that the hypophagic impact of ghrelin was probably mediated by D1 and CB 1 receptors within neonatal broilers. Keywords: Ghrelin, Cannabinoid, Dopamine, Broiler chicken, Food intake INTRODUCTION Appetite and energy expenditure are controlled using central and peripheral neurons to modulate the ingestion response. The feeding behavior of avian is regulated by several peptides (Kaneko et al. 2012). However, a number of these regulatory mechanisms are different among animals. As a basic catecholamine neurotransmitter within the brain, Dopamine (DA) plays an essential role in appetite regulation. Five distinct Dopaminergic (DAergic) receptor subtypes \ have at least been recognized (D 1-D5) in the ventral tegmental area, hypothalamus, and substantia nigra (Cadet et al. 2010). The most abundant DA receptors within the brain are the D1 and D 2 receptors. The DAergic system engages in numerous physiological functions (e.g. cognition, locomotor activity, food intake, and emotion (Madhavan et al. 2013). Food intake is reduced in rats by D1 and D 2 receptors (Volkow et al. 2011). Also, D1 receptors in chickens mediate the DA-induced hypophagia, while other receptors (D 2-D4) may influence appetite regulation (Zendehdel et al. 2016). The central feeding behavior is documented to be not regulated by a single neuropeptide. Also, other neurotransmitters on feeding status are in interaction with a wide distributed neural network (Irwin et al. 2008). Ghrelin was detected in the brain, lung, stomach, proventriculus, spleen, (Pingwen et al. 2011), breast muscle, small intestine, and abdominal fat, (Kaiya et al. 2011), provoking the release of the growth hormone (GH) via GH secretagogue receptors (GHS-R) (Richards, 2003). The subtypes of the ghrelin receptor detected in broilers include GHS-R1aV (homologous to mammalian GHS-R1b), GHS-R1tv, and GHS-R1a ad (Jonaidi et al. 2002). Ghrelin ICV or systemic injection enhances the feeding behavior of laboratory animals (Kaiya et al. 2013), while it inhibits that of meat-type chicken (Furuse et al. 2001; Saito et al. 2005; Zendehdel et al. 2014) and Japanese quail (Shousha et al. 2005). It has been 19 years since the discovery of Ghrelin; however, its role has not yet been fully investigated because of the numerous physiological functions in animals. Moreover, the interaction between ghrelin and other neurotransmitters remains yet to be revealed (Shousha et al. 2005). The endocannabinoids are expressed in the peripheral nervous system (PNS), immune cells and tissues, and CNS (Hassanpour et al. 2015). The ICV administration of CB agonists raises the food intake of rodents, whereas selective CB 1 receptor antagonist (SR141716A) diminished that I of rats (Chen et al. 2006). The ICV injection of CB 1 or CB 2 cannabinoid receptors agonists (2-AG or JWH015) enhances the feeding behavior in layers (Alizadeh et al. 2015), whereas only CB 2 receptors can be effective for broilers (Emadi et al. 2011). Also, the injection of the AM251 (inverse CB 1 receptors agonist) attenuates broiler food intake (Novoseletsky et al. 2011). The ghrelin and DAergic receptors are co-expressed in the CNS neurons (Kern et al. 2015). GHS-R1a forms heteromers with D 1 receptors in hypothalamic neurons and GHS-R1a: D 2 receptors signaling is essential in D 1 receptors agonist-induced hypophagia (Kern et al. 2012). GHSR KO mice treated with a selective GHS-R1a antagonist are resistant to the anorexigenic effects of the D 2 receptors agonist (Kern et al. 2012). By modulating the DAergic reward pathway from VTA to nucleus accumbens (NAcc), the central ghrelin system engages in food intake (Salahpour et al. 2012). In the mice, the hippocampal D 1 receptor signaling is dependent upon the ghrelin receptor (Kern et al. 2015). Ghrelin injection to the VTA and NAcc increases the food intake and extracellular dopamine in mice (Skibicka et al. 2012). The mesolimbic dopamine system’s ghrelin-induced activation in mice is decreased by CB receptor antagonist ICV injection (Kalafateli et al. 2018). The hypothalamic ECB content of CB 1 KO or in rimonabant-treated mice is elevated by ghrelin (Lim et al. 2013). To date, several reports have been provided on the neurotransmitter impacts on food intake among mammalian; however, the food intake aspects of avian remain yet to be revealed (Zendehdel and Hassanpour , 2014; Novoseletsky et al. 2011). For instance, ghrelin plays an anorexigenic role in rats (Kaiya et al. 2011). For birds, however, ghrelin serves as an anorexigenic neurotransmitter (Saito et al. 2005; Zendehdel and Hassanpour, 2014). It is essential to understand the interaction between ghrelin in avian and other neurotransmitters. According to the literature, the engagement of DAergic and CBergic systems in ghrelin-induced hypophagia in broiler avian has not been reported. To shed light on the mechanism that underlies the unique function of ghrelin in chicks, the relationship of ghrelin with the DAergic and CBergic systems is demonstrated for the first time in the present study by investigating the roles of D1-D4 and CB1/CB2 receptors in the ghrelin-induced food intake suppression of some 5-day-old broiler chickens. MATERIALS AND METHODS Animals Four hundred forty-one-day-old broiler chickens of a local hatchery (ROSS 308) were obtained (Mahan Co., Iran). The chickens were kept within stabilizing electrically-heated batteries at 32± 1 ºC and a relative humidity of 40-50% for a 23:1 light/dark schedule (Olanrewaju et al. 2006) as flocks for two days. Then, they were randomly grouped, moved to individual cages, and provided with a commercial diet provided. During the study, the entire broilers were provided with diets and fresh water ad libitum access-. The birds were deprived of food (FD 3) three hours before injections; however, water was available. At the age of five days, ICV injections were applied. Experimental drugs The drugs included ghrelin, AMI-193 (D 2 receptor antagonist), SCH 23390 (D 1 receptor antagonist), L-741,742 (D 4 receptor antagonist), NGB2904 (D 3 receptor antagonist), 6-OHDA (6-hydroxy dopamine), L-DOPA (precursor of dopamine), 6-OHDA (6-hydroxy dopamine) , AM630 (CB 2 receptor antagonist) , [D-Lys-3]-GHRP-6 (ghrelin antagonist), and Evans blue which was obtained from U.S. Sigma-Aldrich Company and U.K. Tocris Company. The drugs were all dissolved in absolute dimethyl sulfoxide (DMSO) before they were diluted with 0.85 % saline with a 1/250 ratio (0.4% DMSO) of the Evans blue (0.1%) content This DMSO ratio has no cytotoxic impacts (Blevins et al. 2002; Qi et al. 2008) . Evans blue-containing DMSO/Saline was utilized as the control group. ICV injection protocol The birds were divided randomly into ten groups, each of which was composed of four sub- groups (i.e., n=44). In each experiment, an ICV injection was performed on each chicken through a microsyringe (Hamilton, Switzerland) with no anesthesia according to the methods proposed by Davis et al. (1979) and Furuse et al. (1997). In summary, the chicken heads were held using an acrylic device with a 45-degree bill holder and a parallel calvarium to the table surface, according to Van Tienhoven and Juhasz (1962). No physiological stress was induced in neonatal chickens in this technique (Furuse et al. 1999). Eventually, the chickens were sacrificed in order to measure injection accuracy. Feeding experiments The present study designed ten experiments in order to identify the possible impacts of particular dopaminergic receptors (i.e., D1, D2, D3, and D 4) on the hypophagic impact of ghrelin for FD 3 neonatal broiler chickens.
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