The dopamine antagonist flupentixol does not alter ghrelin-induced food intake in rats
Introduction
Food intake is complexly regulated via homeostatic and hedonic pathways, the latter are considered to play a role in the development of obesity (Rui, 2013, Berthoud, 2012, Saper et al., 2002). It is therefore important to further elucidate non homeostatic mechanisms of food intake.
Ghrelin is a 28 amino acid peptide that plays a role in the regulation of homeostatic and non-homeostatic feeding (Menzies et al., 2013). Ghrelin is predominantly produced by gastric X/A-like cells and was first isolated from the rat stomach in 1999 by Kojima et al. (Kojima et al., 1999). Two major circulating forms of ghrelin are known: des-octanoyl ghrelin (desacyl-ghrelin) and n-octanoyl ghrelin (ghrelin), which is the form that stimulates food intake (Hosoda et al., 2000, Inhoff et al., 2008). The enzyme catalyzing the acylation of ghrelin was recently discovered and named ghrelin-o-acyltransferase (Yang et al., 2008, Gutierrez et al., 2008). Peripherally injected ghrelin acts via the vagus nerve to centrally to stimulate food intake (Date, 2012). It is important to note that ghrelin is the only known peripherally produced and centrally acting peptide that stimulates food intake in both rodents and humans (Nakazato et al., 2001, Tschöp et al., 2000, Wang et al., 2002, Kobelt et al., 2005, Wren et al., 2001). Acute peripheral and central injections of ghrelin in rodents lead to a rapid orexigenic response (Wren et al., 2000) which was maintained after continuous injection of ghrelin over a period of two weeks (Salome et al., 2009). This orexigenic effect is also observed in humans (Wren et al., 2001). Ghrelin exerts its orexigenic action through activation of the growth hormone secretagogue receptor type 1a (GHS-R1a), renamed ghrelin receptor (GRLN, Davenport et al., 2005). GRLN is widely distributed in the brain with prominent expression in the hypothalamus (Muccioli et al., 2007), and was also found in mesolimbic structures (Zigman et al., 2006, Skibicka et al., 2011, Abizaid et al., 2006).
The mesolimbic dopamine system originates from dopaminergic neurons in the ventral tegmental area (VTA) that project to cortico-limbic structures, like the nucleus accumbens (NAc). The mesolimbic dopamine system enhances motivation behavior and contributes to the development of addiction (Snape and Engel, 1988, Schultz et al., 1997).
It has been shown that palatable foods triggers dopamine release in the mesolimbic reward system including the NAc (Kawahara et al., 2013). Similarly, peripheral and central injection of ghrelin increases the dopamine concentration in the NAc as measured by microdialysis (Jerlhag, 2008) and a striatal dopamine depletion suppresses ghrelin's ability to elicit food-reinforced behavior (Weinberg et al., 2011). Furthermore, ghrelin stimulates food intake when microinjected into brain areas involved in reward-related behavior, like the VTA or the NAc (Naleid et al., 2005). Microinjection of ghrelin into the VTA of rats especially enhances the rats' motivation to obtain palatable chow (King et al., 2011). Taken together, these data suggest a link between the ghrelinergic system and the dopaminergic system in the mediation of non-homeostatic food intake (Abizaid, 2009). There is converging evidence that ghrelin and dopamine interact in the hedonic regulation of food intake.
The aim of our present study was to investigate the role of dopamine in non-homeostatic pathways of ghrelin-induced food intake. We hypothesized that the blockade of dopamine receptors attenuates the ghrelin-induced food intake. Therefore, we blocked dopamine receptors using the dopamine pan-antagonist, flupentixol. We further used a rat model for reward-driven food intake and examined the role of ghrelin and dopamine in this context.
Section snippets
1. Animals
Male Sprague–Dawley rats (Harlan-Winkelmann Co., Borchen, Germany) weighing 240–300 g were group-housed (4 rats/cage) under conditions of controlled illumination (12:12 h light/dark cycle, lights on/off: 6:30 a.m./6:30 p.m.), humidity and temperature (22 ± 2 °C). Animals were fed with a standard rat chow (Altromin™, Lage, Germany) and tap water ad libitum unless otherwise specified. All animals were trained daily to become accustomed to the experimental conditions. Animal care and experimental
Rats choose preferred chow over standard chow
When allowed to choose, rats consumed greater amounts of preferred chow over the standard chow as reflected in a ~ 15-times greater intake (at light phase) of preferred compared to standard chow (Fig. 1 and Table 1).
Flupentixol does not attenuate peripheral ghrelin-induced food intake in rats fed standard rat chow
Ghrelin significantly increased food intake within the first half hour after ip injection compared to the vehicle treated rats (1.40 ± 0.38 vs. 0.23 ± 0.17 g/rat, P < 0.05; Fig. 2 and Table 2). This effect was still visible at 5 h after peptide injection (1.63 ± 0.35 vs. 0.48 ± 0.17 g/rat, P <
Discussion
In the present study ghrelin reliably increased the intake of standard rat chow, while the intake of preferred chow was not further stimulated by ip ghrelin. Icv administered ghrelin led to a delayed increase in the intake of preferred chow. The dopamine antagonist, flupentixol did not affect the ghrelin-induced food intake. During the first half of the dark phase flupentixol significantly increased the intake of standard chow, whereas a decrease in food intake was observed during the second
Acknowledgments
We are grateful to Reinhardt Lommel for technical support. This work was supported by grants from the Charité-Universitätsmedizin Berlin (2010-043).
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