Elsevier

Neuropeptides

Volume 53, October 2015, Pages 19-27
Neuropeptides

The dopamine antagonist flupentixol does not alter ghrelin-induced food intake in rats

https://doi.org/10.1016/j.npep.2015.08.007Get rights and content

Highlights

  • We examine the influence of the dopamine antagonist flupentixol on ghrelin-induced food intake.

  • As a model for reward driven food intake we introduce a special kind of preferred chow.

  • Ghrelin increases the intake of standard chow but not of preferred chow.

  • Flupentixol does not affect ghrelin-induced food intake.

Abstract

It has been shown that dopamine antagonists suppress the ghrelin-induced increased motivation to work for food. The aim of this study was to investigate the influence of the dopamine antagonist flupentixol on ghrelin-induced food intake. Ad libitum fed male Sprague–Dawley (SD) rats were injected intraperitoneally (ip) with vehicle plus vehicle, vehicle plus ghrelin (13 μg/kg), 0.25 mg/kg or 0.5 mg/kg flupentixol plus ghrelin, or 0.25 mg/kg or 0.5 mg/kg flupentixol plus vehicle. In a second experiment, intracerebroventricularly (icv) cannulated rats received an ip injection of vehicle (0.15 M NaCl) or flupentixol (0.25 mg/kg) and 20 min later an icv injection of vehicle or ghrelin (1 μg/rat). Both experiments were performed twice: first, rats were offered only standard chow, while in the second experiment they could choose between standard chow and a palatable/preferred chow. Cumulative light phase food intake was assessed for 7 h. Ip as well as icv injected ghrelin reliably increased intake of standard chow. Flupentixol did not affect ghrelin-induced intake of standard chow. Ip injected ghrelin failed to increase the intake of palatable chow, whereas icv injected ghrelin did. This effect was not blocked by ip flupentixol. In summary, ip administered ghrelin did not increase the intake of chow the rats preferred; whereas icv injected ghrelin further stimulated the intake of preferred chow suggesting a direct central mediation of this effect. Our results show that the dopamine antagonist flupentixol does not influence ghrelin-induced feeding in our choice paradigm.

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).

References (67)

  • A.M. Naleid et al.

    Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens

    Peptides

    (2005)
  • K.L. Nowend et al.

    D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption

    Pharmacol. Biochem. Behav.

    (2001)
  • M. Perello et al.

    Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner

    Biol. Psychiatry

    (2010)
  • D. Quarta et al.

    Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens

    Neurochem. Int.

    (2009)
  • J.D. Salamone et al.

    Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine

    Behav. Brain Res.

    (2002)
  • C.B. Saper et al.

    The need to feed: homeostatic and hedonic control of eating

    Neuron

    (2002)
  • K.P. Skibicka et al.

    Ghrelin directly targets the ventral tegmental area to increase food motivation

    Neuroscience

    (2011)
  • K.P. Skibicka et al.

    Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA-accumbens projection mediates ghrelin's effect on food reward but not food intake

    Neuropharmacology

    (2013)
  • B.M. Snape et al.

    Ethanol enhances the calcium-dependent stimulus-induced release of endogenous dopamine from slices of rat striatum and nucleus accumbens in vitro

    Neuropharmacology

    (1988)
  • D. Stevanovic et al.

    Consummatory behavior and metabolic indicators after central ghrelin injections in rats

    Regul. Pept.

    (2008)
  • M. Tanaka et al.

    Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders

    J. Psychiatr. Res.

    (2003)
  • L. Wang et al.

    Peripheral ghrelin selectively increases Fos expression in neuropeptide Y-synthesizing neurons in mouse hypothalamic arcuate nucleus

    Neurosci. Lett.

    (2002)
  • Z.Y. Weinberg et al.

    Hydroxydopamine lesions of the ventral tegmental area suppress ghrelin's ability to elicit food-reinforced behavior

    Neurosci. Lett.

    (2011)
  • J. Yang et al.

    Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone

    Cell

    (2008)
  • A. Abizaid

    Ghrelin and dopamine: new insights on the peripheral regulation of appetite

    J. Neuroendocrinol.

    (2009)
  • A. Abizaid et al.

    Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

    J. Clin. Invest.

    (2006)
  • G. Addolorato et al.

    Relationship between ghrelin levels, alcohol craving, and nutritional status in current alcoholic patients

    Alcohol. Clin. Exp. Res.

    (2006)
  • B.A. Baldo et al.

    Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat

    Psychopharmacology (Berlin)

    (1999)
  • M.F. Barbano et al.

    Differential regulation of the consummatory, motivational and anticipatory aspects of feeding behavior by dopaminergic and opioidergic drugs

    Neuropsychopharmacology

    (2006)
  • I. Bednar et al.

    Involvement of dopamine in inhibition of food intake by cholecystokinin octapeptide in male rats

    J. Neuroendocrinol.

    (1991)
  • J.A. Beeler et al.

    Tonic dopamine modulates exploitation of reward learning

    Front. Behav. Neurosci.

    (2010)
  • M. Benoit-Marand et al.

    Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo

    J. Neurosci.

    (2001)
  • K.C. Berridge et al.

    Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: implications for arousal and anhedonia hypotheses of dopamine function

    Behav. Neurosci.

    (1989)
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