Orexigenic Peptide Ghrelin Research Articles

Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1.

During childhood and adolescence, a number of factors, including age, puberty, sex, race, and body composition, may contribute to differences in satiety, food intake, and appetite-related peptides. These peptides include the orexigenic peptide ghrelin and anorexigenic gut peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). For example, lower fasting ghrelin levels, lower postprandial ghrelin suppression, and blunted PYY and GLP-1 responses to food intake could contribute to a dysregulation of appetite in already obese children and adolescents. Whereas, changes in these peptides observed during puberty could facilitate growth. A greater understanding of the major moderating factors of appetite-related peptides in the pediatric population is essential to improve interpretation of study findings and for effective tailoring of strategies targeting appetite control to individuals. While more studies are needed, there is some evidence to suggest that exercise-based lifestyle interventions could be a potential therapeutic strategy to improve appetite-peptide profiles in overweight and obese children and adolescents. The aim of this review is (i) to discuss the potential moderating factors of ghrelin, PYY, and GLP-1, including age and puberty, sex, race and body composition; and (ii) to examine the effects of exercise interventions on these appetite-related gut peptides in children and adolescents.

Ghrelin receptor modulates T helper cells during intestinal inflammation.

The orexigenic peptide ghrelin has anti-inflammatory properties in colitis, however, the mechanism of action and the immune cells targeted remain still to be elucidated. Here, we assessed the possible effect of ghrelin on T helper (Th) cells in a T cell transfer model of chronic colitis. Disease was induced in the recombination activating gene 1 knockout mice (Rag1(-/-) ) by adoptive transfer of naïve Th cells from ghrelin receptor knockout mice (GRLN-R(-/-) ) or littermate wild-type (WT) mice. The course and severity of colitis was assessed by monitoring body weight, diarrhea score, histological analysis, gene expression, and flow cytometry analysis. The possible effects of ghrelin on Th cell proliferation, polarization, and apoptosis was examined invitro. Our data showed that Rag1(-/-) mice injected with GRLN-R(-/-) Th cells displayed increased severity of colitis compared to mice injected with WT Th cells. In addition, Rag1(-/-) mice injected with GRLN-R(-/-) Th cells had significantly higher intestinal inflammation and increased accumulation of Th1 and Th17 cells in the colon. In vitro, ghrelin directly affected proliferation of Th cells and induced apoptosis whereas it did not influence Th cell polarization. Our observations suggest that ghrelin modulates Th effector cells in the gut controlling proliferation and inducing apoptosis. Our findings further support the use of ghrelin as a novel therapeutic option to treat intestinal inflammatory diseases.

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice

A high-fat diet (HFD) induces inflammation in systemic organs including the hypothalamus, resulting in obesity and diabetes. The vagus nerve connects the visceral organs and central nervous system, and the gastric-derived orexigenic peptide ghrelin transmits its starvation signals to the hypothalamus via the vagal afferent nerve. Here we investigated the inflammatory response in vagal afferent neurons and the hypothalamus in mice following one day of HFD feeding. This treatment increased the number of macrophages/microglia in the nodose ganglion and hypothalamus. Furthermore, one-day HFD induced expression of Toll-like receptor 4 in the goblet cells of the colon and upregulated mRNA expressions of the proinflammatory biomarkers Emr1, Iba1, Il6, and Tnfα in the nodose ganglion and hypothalamus. Both subcutaneous administration of ghrelin and celiac vagotomy reduced HFD-induced inflammation in these tissues. HFD intake triggered inflammatory responses in the gut, nodose ganglion, and subsequently in the hypothalamus within 24 h. These findings suggest that the vagal afferent nerve may transfer gut-derived inflammatory signals to the hypothalamus via the nodose ganglion, and that ghrelin may protect against HFD-induced inflammation.

Knockdown of central ghrelin O-acyltransferase by vivo-morpholino reduces body mass of rats fed a high-fat diet

The enzyme ghrelin O-acyltransferase (GOAT) activates the orexigenic peptide ghrelin by transferring an acyl group from fatty acids to the serine-3 residue of the ghrelin molecule. This allows ghrelin to bind to its only known receptor, the growth hormone secretagogue receptor type 1a (GHSR1a). While studies have examined the hypothalamic transcriptional response of GOAT to metabolic challenge in mice, little has been examined in the rat hypothalamus. Furthermore, it has not been possible to identify the role of central GOAT separate from that of the periphery, since previous studies either knocked out GOAT system-wide or administered a GOAT inhibitor intraperitoneally. To determine if central GOAT expression is modulated by changes in energy state, we subjected rats to either forty-eight hours of food deprivation or three weeks of food restriction and found that GOAT mRNA increases significantly in both the hypothalamus and the stomach fundus in response to both metabolic challenges. We also found increases in hypothalamic ghrelin mRNA and stomach GHSR1a mRNA in response to food deprivation, as well as increases in hypothalamic GHSR1a mRNA in response to food restriction. We then conducted a second study where we continuously infused amorpholino antisense oligonucleotide into the lateral ventricles of rats to knock-down GOAT centrally while the animals were exposed to a high fat diet. Our results show that rats receiving the GOAT antisense gained less weight, and decreased their caloric efficiency when eating a high fat diet compared to control animals. These data suggest that central GOAT plays a role in modulating metabolism in rats.

Effects of Cigarette Smoking on Plasma Concentration of the Appetite-Regulating Peptide Ghrelin

Background: Weight gain is a common but only a partially understood consequence of smoking cessation. Existing data suggest modulating effects of the orexigenic peptide ghrelin on food intake. The aim of the present study was to investigate the effect of tobacco withdrawal on plasma concentration of acetylated and total ghrelin. Methods: Fifty four normal-weighted smokers and 30 non-smoking healthy controls were enrolled in our study. Concentrations of acetylated and total ghrelin were measured in blood plasma drawn two hours after a standardized meal and three hours after the smokers smoked their last cigarette. The severity of tobacco addiction was assessed based on cotinine plasma concentration, the Fagerström Test for Nicotine Dependence (FTND) and the number of cigarettes smoked per day. Results: The plasma concentration of acetylated ghrelin, but not total ghrelin, was significantly higher in smokers than in non-smokers. Moreover, we found significant negative correlations between acetylated ghrelin and all measures of the severity of nicotine dependence. Conclusions: Early abstinence from tobacco smoking seems to be associated with increased plasma concentration of the orexigenic peptide acetylated ghrelin. This could be one reason for increased food craving during nicotine withdrawal and subsequent weight gain. Smokers might compensate these effects by increasing tobacco intake.

Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

BackgroundHedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown.MethodsTo explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale.ResultsThe anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one.ConclusionsWhen motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

Leptin And Ghrelin – The New Old Players In Obesity And Depression

Summary The participation of the anorexigenic peptide leptin and the orexigenic peptide ghrelin in the pathogenesis of metabolic syndrome and obesity is well studied. In this review, we are taking a look at the structure, anatomical expression, regulation, receptors and physiological functions of these two neuropeptides. Leptin is produced almost exclusively in adipose tissue. It acts on the brain and is a key element in long-term regulation of energy balance. Leptin suppresses appetite and reduces body weight. Besides its central effects, important aspects of its action on peripheral tissues have been discovered recently: direct regulation of immune cells, pancreatic beta cells, adipocytes and muscle cells. Ghrelin is an endogenous ligand for the active form of the growth hormone receptor (GHS-R1a) and stimulates food intake and growth hormone secretion. We focus on the role of leptin and ghrelin in central nervous system neural mechanisms that are associated with depression. Studying new aspects of these two neuropeptides aims to expand our knowledge of the pathogenesis and therapeutic approaches to diseases with which they are associated: obesity, depression, type 2 diabetes, essential hypertension, and more.

Role of appetite-regulating peptides in the pathophysiology of addiction: implications for pharmacotherapy.

Food intake and appetite are regulated by various circulating hormones including ghrelin and glucagon-like-peptide 1 (GLP-1). Ghrelin, mainly released from the stomach, increases food intake, induces appetite, enhances adiposity as well as releases growth hormone. Hypothalamic “ghrelin receptors” (GHS-R1A) have a critical role in food intake regulation, but GHS-R1A are also expressed in reward related areas. GLP-1 is produced in the intestinal mucosa as well as in the hindbrain in response to nutrient ingestion. This gut-brain hormone reduces food intake as well as regulates glucose homeostasis, foremost via GLP-1 receptors in hypothalamus and brain stem. However, GLP-1 receptors are expressed in areas intimately associated with reward regulation. Given that regulation of food and drug intake share common neurobiological substrates, the possibility that ghrelin and GLP-1 play an important role in reward regulation should be considered. Indeed, this leading article describes that the orexigenic peptide ghrelin activates the cholinergic–dopaminergic reward link, an important part of the reward systems in the brain associated with reinforcement and thereby increases the incentive salience for motivated behaviors via this system. We also review the role of ghrelin signaling for reward induced by alcohol and addictive drugs from a preclinical, clinical and human genetic perspective. In addition, the recent findings showing that GLP-1 controls reward induced by alcohol, amphetamine, cocaine and nicotine in rodents are overviewed herein. Finally, the role of several other appetite regulatory hormones for reward and addiction is briefly discussed. Collectively, these data suggest that ghrelin and GLP-1 receptors may be novel targets for development of pharmacological treatments of alcohol and drug dependence.

Nicotine administration in healthy non-smokers reduces appetite but does not alter plasma ghrelin

We studied whether suppressed secretion of the orexigenic peptide ghrelin might be involved in the anorexigenic effects of nicotine. Fifty healthy non-smokers chewed gums containing 2 mg nicotine, or no nicotine in a double-blind randomised crossover design in two independent studies. Plasma nonacylated ghrelin was not significantly affected by nicotine after 30 and 60 min. Increased blood pressure and decreased appetite ratings confirmed a biological nicotine effect. These results do not support a key role of peripheral ghrelin secretion in weight changes related to smoking or smoking cessation, but do not rule out that central nervous system ghrelin is involved.

S27 * INNOVATIVE TECHNIQUES IN HUMAN LABORATORY ALCOHOL RESEARCH

S27 * INNOVATIVE TECHNIQUES IN HUMAN LABORATORY ALCOHOL RESEARCH

Ghrelin and Nicotine Stimulate Equally the Dopamine Release in the Rat Amygdala

The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward processes and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Ghrelin and nicotine activates the mesolimbicocortical dopaminergic pathways via growth hormone secretagogue receptors (GHS-R1A) and nicotinic acetylcholine receptors (nAchR), respectively, resulting in the release of dopamine in the nucleus accumbens, the amygdala and the prefrontal cortex. In the present study an in vitro superfusion of rat amygdalar slices was performed in order to investigate the direct action of ghrelin and nicotine on the amygdalar dopamine release. Ghrelin increased significantly the dopamine release from the rat amygdala following electrical stimulation. This effect was inhibited by both the selective GHS-R1A antagonist GHRP-6 and the selective nAchR antagonist mecamylamine. Under the same conditions, nicotine also increased significantly the dopamine release from the rat amygdala. This effect was antagonized by mecamylamine, but not by GHRP-6. Co-administration of ghrelin and nicotine induced a similar increase of amygdalar dopamine release. This stimulatory effect was partially reversed by both GHRP-6 and mecamylamine. The present results demonstrate that both ghrelin and nicotine stimulates directly the dopamine release in the amygdala, an important dopaminergic target area of the mesolimbicocortical pathway.

Ghrelin amplifies the nicotine-induced dopamine release in the rat striatum

The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward mechanisms and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Nicotine activates the mesencephalic dopaminergic neurons via nicotinic acetylcholine receptors (nAchR). Ghrelin stimulates the dopaminergic neurons via growth hormone secretagogue receptors (GHS-R1A) in the ventral tegmental area and the substantia nigra pars compacta resulting in the release of dopamine in the ventral and dorsal striatum, respectively. In the present study an in vitro superfusion of rat striatal slices was performed, in order to investigate the direct action of ghrelin on the striatal dopamine release and the interaction of ghrelin with nicotine through this neurotransmitter release. Ghrelin increased significantly the dopamine release from the rat striatum following electrical stimulation. This stimulatory effect was reversed by both the selective nAchR antagonist mecamylamine and the selective GHS-R1A antagonist GHRP-6. Nicotine also increased significantly the dopamine release under the same conditions. This stimulatory effect was antagonized by mecamylamine, but not by GHRP-6. Ghrelin further stimulated the nicotine-induced dopamine release and this effect was abolished by mecamylamine and was partially inhibited by GHRP-6. The present results demonstrate that ghrelin stimulates directly the dopamine release and amplifies the nicotine-induced dopamine release in the rat striatum. We presume that striatal cholinergic interneurons also express GHS-R1A, through which ghrelin can amplify the nicotine-induced dopamine release in the striatum. This study provides further evidence of the impact of ghrelin on the mesolimbic and nigrostriatal dopaminergic pathways. It also suggests that ghrelin signaling may serve as a novel pharmacological target for treatment of addictive and neurodegenerative disorders.

Ghrelin and NUCB2/nesfatin-1 are expressed in the same gastric cell and differentially correlated with body mass index in obese subjects

The orexigenic peptide ghrelin and the anorexigenic peptide nesfatin-1 are expressed by the same endocrine cell of the rat stomach, the X/A-like cell. However, data in humans are lacking, especially under conditions of obesity. We collected gastric tissue of obese patients undergoing sleeve gastrectomy and investigated the expression of nesfatin-1 and ghrelin in the gastric oxyntic mucosa by immunofluorescence. Nesfatin-1 immunoreactivity was detected in the human oxyntic mucosa in cells with an endocrine phenotype. A major portion of nesfatin-1 immunoreactive cells (78%) co-localized with ghrelin indicating the occurrence in human X/A-like cells. In patients with very high body mass index (BMI 55-65kg/m(2)), the number of nesfatin-1 immunoreactive cells/low-power field was significantly higher than in obese patients with lower BMI (40-50kg/m(2), 118±10 vs. 82±11, p<0.05). On the other hand, the number of ghrelin immunoreactive cells was significantly reduced in obese patients with higher compared to lower BMI (96±12 vs. 204±21, p<0.01). Also the ghrelin-acylating enzyme ghrelin-O-acyltransferase decreased with increasing BMI. In conclusion, nesfatin-1 immunoreactivity is also co-localized with ghrelin in human gastric X/A-like cells giving rise to a dual role of this cell type with differential effects on stimulation and inhibition of appetite dependent on the peptide released. The expression of these two peptides is differentially regulated under obese conditions with an increase of nesfatin-1 and a decrease of ghrelin immunoreactivity with rising BMI pointing towards an adaptive change of expression that may counteract further body weight increase.

Glutamate and GABA in Appetite Regulation

Appetite is regulated by a coordinated interplay between gut, adipose tissue, and brain. A primary site for the regulation of appetite is the hypothalamus where interaction between orexigenic neurons, expressing Neuropeptide Y/Agouti-related protein, and anorexigenic neurons, expressing Pro-opiomelanocortin cocaine/Amphetamine-related transcript, controls energy homeostasis. Within the hypothalamus, several peripheral signals have been shown to modulate the activity of these neurons, including the orexigenic peptide ghrelin and the anorexigenic hormones insulin and leptin. In addition to the accumulated knowledge on neuropeptide signaling, presence and function of amino acid neurotransmitters in key hypothalamic neurons brought a new light into appetite regulation. Therefore, the principal aim of this review will be to describe the current knowledge of the role of amino acid neurotransmitters in the mechanism of neuronal activation during appetite regulation and the associated neuronal-astrocytic metabolic coupling mechanisms. Glutamate and GABA dominate synaptic transmission in the hypothalamus and administration of their receptors agonists into hypothalamic nuclei stimulates feeding. By using 13C High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance spectroscopy based analysis, the Cerdán group has shown that increased neuronal firing in mice hypothalamus, as triggered by appetite during the feeding-fasting paradigm, may stimulate the use of lactate as neuronal fuel leading to increased astrocytic glucose consumption and glycolysis. Moreover, fasted mice showed increased hypothalamic [2-13C]GABA content, which may be explained by the existence of GABAergic neurons in key appetite regulation hypothalamic nuclei. Interestingly, increased [2-13C]GABA concentration in the hypothalamus of fasted animals appears to result mainly from reduction in GABA metabolizing pathways, rather than increased GABA synthesis by augmented activity of the glutamate-glutamine-GABA cycle.

Intracerebroventricular Administration of Metformin Inhibits Ghrelin-Induced Hypothalamic AMP-Kinase Signalling and Food Intake

Background/Aims: The antihyperglycaemic drug metformin reduces food consumption through mechanisms that are not fully elucidated. The present study investigated the effects of intracerebroventricular administration of metformin on food intake and hypothalamic appetite-regulating signalling pathways induced by the orexigenic peptide ghrelin. Methods: Rats were injected intracerebroventricularly with ghrelin (5 µg), metformin (50, 100 or 200 µg), 5-amino-imidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 25 µg) and L-leucine (1 µg) in different combinations. Food intake was monitored during the next 4 h. Hypothalamic activation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), regulatory-associated protein of mTOR (Raptor), mammalian target of rapamycin (mTOR) and p70 S6 kinase 1 (S6K) after 1 h of treatment was analysed by immunoblotting. Results: Metformin suppressed the increase in food consumption induced by intracerebroventricular ghrelin in a dose-dependent manner. Ghrelin increased phosphorylation of hypothalamic AMPK and its targets ACC and Raptor, which was associated with the reduced phosphorylation of mTOR. The mTOR substrate, S6K, was activated by intracerebroventricular ghrelin despite the inhibition of mTOR. Metformin treatment blocked ghrelin-induced activation of hypothalamic AMPK/ACC/Raptor and restored mTOR activity without affecting S6K phosphorylation. Metformin also reduced food consumption induced by the AMPK activator AICAR while the ghrelin-triggered food intake was inhibited by the mTOR activator L-leucine. Conclusion: Metformin could reduce food intake by preventing ghrelin-induced AMPK signalling and mTOR inhibition in the hypotalamus.

Attenuation of cocaine‐induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors

Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine-stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for GHR and GHR receptors (GHR-Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats, sustaining either pharmacologic antagonism or genetic ablation of GHR-Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR-R1 receptor antagonist), and 20 minutes later, with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine-induced hyperlocomotion. In a second study, adult wild-type (WT) or mutant rats sustaining ENU-induced knockout of GHR-R [GHR-R ((-/-) )] received daily injections (i.p.) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR-R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR-R function in the GHR-R ((-/-) ) rats, a separate feeding experiment was conducted in which WT rats, but not GHR-R ((-/-) ) rats, were noted to eat more after a systemic injection of 15 nmol GHR than after vehicle. These results suggest that GHR-R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. GHR is an orexigenic gut peptide that is transported across the blood-brain barrier and interacts with GHR-Rs located on ventral tegmental dopamine neurons.

The Ghrelin Signalling System Is Involved in the Consumption of Sweets

The gastric-derived orexigenic peptide ghrelin affects brain circuits involved in energy balance as well as in reward. Indeed, ghrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link. It has been hypothesized that there is a common reward mechanism for alcohol and sweet substances in both animals and humans. Alcohol dependent individuals have higher craving for sweets than do healthy controls and the hedonic response to sweet taste may, at least in part, depend on genetic factors. Rat selectively bred for high sucrose intake have higher alcohol consumption than non-sucrose preferring rats and vice versa. In the present study a group of alcohol-consuming individuals selected from a population cohort was investigated for genetic variants of the ghrelin signalling system in relation to both their alcohol and sucrose consumption. Moreover, the effects of GHS-R1A antagonism on voluntary sucrose- intake and operant self-administration, as well as saccharin intake were investigated in preclinical studies using rodents. The effects of peripheral grelin administration on sucrose intake were also examined. Here we found associations with the ghrelin gene haplotypes and increased sucrose consumption, and a trend for the same association was seen in the high alcohol consumers. The preclinical data show that a GHS-R1A antagonist reduces the intake and self-administration of sucrose in rats as well as saccharin intake in mice. Further, ghrelin increases the intake of sucrose in rats. Collectively, our data provide a clear indication that the GHS-R1A antagonists reduces and ghrelin increases the intake of rewarding substances and hence, the central ghrelin signalling system provides a novel target for the development of drug strategies to treat addictive behaviours.

Expression of the gene encoding the ghrelin receptor in rats selected for differential alcohol preference

The mechanisms involved in alcohol use disorder, a chronic relapsing brain disorder, are complex and involve various signalling systems in the brain. Recently, the orexigenic peptide ghrelin was shown to be required for alcohol-induced reward, an effect mediated via ghrelin receptors, GHS-R1A, at the level of the cholinergic-dopaminergic reward link. Moreover, ghrelin increases and GHR-R1A antagonists reduce moderate alcohol consumption in mice, and a single nucleotide polymorphism in the GHS-R1A gene has been associated with high alcohol consumption in humans. Therefore, GHS-R1A gene expression and alcohol intake were investigated in high, AA (Alko, Alcohol), versus low, ANA (Alko, Non-Alcohol), alcohol consuming rats as well as in Wistar rats. In the AA and ANA rats plasma ghrelin levels were also measured. GHS-R1A gene expression was increased in AA compared to ANA rats in nucleus accumbens, ventral tegmental area, amygdala, prefrontal cortex and hippocampus. A similar trend was observed in the ventral tegmental area of Wistar rats consuming high amounts of alcohol. Furthermore, the AA rats had significantly smaller reduction of plasma ghrelin levels over time, after several weeks of alcohol exposure, than had the ANA rats. The present study provides further evidence for that the ghrelin signalling system, in particular at the level of the mesocortocolimbic dopamine system, is involved in alcohol consumption, and thus possibly contributes to alcohol use disorder. Therefore the GHS-R1A may constitute a novel candidate for development of new treatment strategies for alcohol dependence.

Is there altered sensitivity to ghrelin-receptor ligands in leptin-deficient mice?: importance of satiety state and time of day

Several fine-tuned and interconnected hypothalamic peptidergic systems orchestrate the regulation of energy homeostasis in the body. The orexigenic peptide ghrelin and the anorexigenic peptide leptin are among the most important, and both have been implicated in the development of eating disorders from obesity to anorexia nervosa. The goal of these studies was to examine the response of leptin-deficient ob/ob mice in ghrelin-receptor ligands in a food intake task. Changes in cumulative food intake were measured after peripheral administration of ghrelin (1 and 2nmol/10g) and the ghrelin-receptor antagonist (D-Lys(3))-GHRP-6 (66.6 and 133.3nmol/10g) in obese and lean control mice during the light and dark cycle as well as in a state of food restriction. Hypothalamic ghrelin and ghrelin-receptor expression was measured in ob/ob and lean mice at two different timepoints. Ghrelin increased food intake in lean and obese mice in the light and dark cycle, whereas the ghrelin-receptor antagonist caused significantly stronger reduction in food intake in obese mice only in the dark cycle. After fasting, ob/ob mice displayed decreased light cycle sensitivity to the anorexigenic effects of the ghrelin-receptor antagonist. Hypothalamic expression levels of ghrelin were unaltered during the light cycle but decreased during the dark cycle in ob/ob mice; whereas, although unchanged in the light cycle, ghrelin-receptor expression was increased in the dark cycle in obese mice. The functionality and sensitivity of the ghrelinergic system is dependent on the time of day and the satiety state in leptin-deficient ob/ob mice.

Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice

Background The orexigenic peptide ghrelin activates the reward systems, specifically the cholinergic–dopaminergic reward link, suggesting that ghrelin may increase the incentive salience of motivated behaviours such as food seeking. Moreover, central ghrelin signalling, involving the growth hormone secretagogue receptor 1A (GHS-R1A), is required for the rewarding properties, as measured by locomotor stimulation, accumbal dopamine release and conditioned place preference, of alcohol, cocaine as well as amphetamine. As the target circuits for other drugs of abuse, including nicotine, in the brain includes this reward link, we sought to determine whether the central ghrelin signalling system is involved in nicotine's activation of this system. Methods This was investigated by studying the effects of peripheral administration of a GHS-R1A antagonist (JMV2959) on the nicotine-induced locomotor simulation, accumbal dopamine release and conditioned place preference. Results In the present study we found that the ability of nicotine to increase the locomotor activity, accumbal dopamine release and to condition place preference were reduced in mice treated with a GHS-R1A antagonist. Conclusion Thus GHS-R1A appears to be required not only for alcohol, cocaine and amphetamine-induced reward, but also for reward induced by nicotine. Our data suggest that the central ghrelin signalling system may constitute a novel potential target for treatment of drug dependence.