Buserelin treatment to rats causes enteric neurodegeneration with moderate effects on CRF-immunoreactive neurons and Enterobacteriaceae in colon, and in acetylcholine-mediated permeability in ileum

The gonadotropin-releasing hormone (GnRH) analog buserelin causes enteric neuronal loss. Acute stress or injection of corticotropin-releasing factor (CRF) affects motility, secretion, and barrier function of the gastrointestinal tract. The aim of the study was to characterize the CRF immunoreactivity in enteric neurons after buserelin treatment, and to evaluate possible effects of enteric neuropathy on gut microbiota, intestinal permeability, and stress response behavior

Influence of ghrelin on the central serotonergic signaling system in mice

AbstractThe central ghrelin signaling system engages key pathways of importance for feeding control, recently shown to include those engaged in anxiety-like behavior in rodents. Here we sought to determine whether ghrelin impacts on the central serotonin system, which has an important role in anxiety. We focused on two brain areas, the amygdala (of importance for the mediation of fear and anxiety) and the dorsal raphe (i.e. the site of origin of major afferent serotonin pathways, including those that project to the amygdala). In these brain areas, we measured serotonergic turnover (using HPLC) and the mRNA expression of a number of serotonin-related genes (using real-time PCR). We found that acute central administration of ghrelin to mice increased the serotonergic turnover in the amygdala. It also increased the mRNA expression of a number of serotonin receptors, both in the amygdala and in the dorsal raphe. Studies in ghrelin receptor (GHS-R1A) knock-out mice showed a decreased mRNA expression of serotonergic receptors in both the amygdala and the dorsal raphe, relative to their wild-type littermates. We conclude that the central serotonin system is a target for ghrelin, providing a candidate neurochemical substrate of importance for ghrelin's effects on mood

Ghrelin increases intake of rewarding food in rodents

We investigated whether ghrelin action at the level of the ventral tegmental area (VTA), a key node in the mesolimbic reward system, is important for the rewarding and motivational aspects of the consumption of rewarding/palatable food. Mice with a disrupted gene encoding the ghrelin receptor (GHS-R1A) and rats treated peripherally with a GHS-R1A antagonist both show suppressed intake of rewarding food in a free choice (chow/rewarding food) paradigm. Moreover, accumbal dopamine release induced by rewarding food was absent in GHS-R1A knockout mice. Acute bilateral intra-VTA administration of ghrelin increased 1-hour consumption of rewarding food but not standard chow. In comparison with sham rats, VTA-lesioned rats had normal intracerebroventricular ghrelin-induced chow intake, although both intake of and time spent exploring rewarding food was decreased. Finally, the ability of rewarding food to condition a place preference was suppressed by the GHS-R1A antagonist in rats. Our data support the hypothesis that central ghrelin signaling at the level of the VTA is important for the incentive value of rewarding food

Hedonic and incentive signals for body weight control

Here we review the emerging neurobiological understanding of the role of the brain’s reward system in the regulation of body weight in health and in disease. Common obesity is characterized by the over-consumption of palatable/rewarding foods, reflecting an imbalance in the relative importance of hedonic versus homeostatic signals. The popular ‘incentive salience theory’ of food reward recognises not only a hedonic/pleasure component (‘liking’) but also an incentive motivation component (‘wanting’ or ‘reward-seeking’). Central to the neurobiology of the reward mechanism is the mesoaccumbal dopamine system that confers incentive motivation not only for natural rewards such as food but also by artificial rewards (eg. addictive drugs). Indeed, this mesoaccumbal dopamine system receives and integrates information about the incentive (rewarding) value of foods with information about metabolic status. Problematic over-eating likely reflects a changing balance in the control exerted by hypothalamic versus reward circuits and/or it could reflect an allostatic shift in the hedonic set point for food reward. Certainly, for obesity to prevail, metabolic satiety signals such as leptin and insulin fail to regain control of appetitive brain networks, including those involved in food reward. On the other hand, metabolic control could reflect increased signalling by the stomach-derived orexigenic hormone, ghrelin. We have shown that ghrelin activates the mesoaccumbal dopamine system and that central ghrelin signalling is required for reward from both chemical drugs (eg alcohol) and also from palatable food. Future therapies for problematic over-eating and obesity may include drugs that interfere with incentive motivation, such as ghrelin antagonists

The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice.

The gastrointestinal peptide glucagon-like peptide 1 (GLP-1) is known to regulate consummatory behavior and is released in response to nutrient ingestion. Analogues of this peptide recently emerged as novel pharmacotherapies for treatment of type II diabetes since they reduce gastric emptying, glucagon secretion as well as enhance glucose-dependent insulin secretion. The findings that GLP-1 targets reward related areas including mesolimbic dopamine areas indicate that the physiological role of GLP-1 extends beyond food intake and glucose homeostasis control to include reward regulation. The present series of experiments was therefore designed to investigate the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on established nicotine-induced effects on the mesolimbic dopamine system in mice. Specifically, we show that treatment with Ex4, at a dose with no effect per se, attenuate nicotine-induced locomotor stimulation, accumbal dopamine release as well as the expression of conditioned place preference in mice. In accordance, Ex4 also blocks nicotine-induced expression of locomotor sensitization in mice. Given that development of nicotine addiction largely depends on the effects of nicotine on the mesolimbic dopamine system these findings indicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for nicotine cessations in humans

Consumption of thylakoid-rich spinach extract reduces hunger, increases satiety and reduces cravings for palatable food in overweight women.

Green-plant membranes, thylakoids, have previously been found to increase postprandial release of the satiety hormone GLP-1, implicated in reward signaling. The purpose of this study was to investigate how treatment with a single dose of thylakoids before breakfast affects homeostatic as well as hedonic hunger, measured as wanting and liking for palatable food (VAS). We also examined whether treatment effects were correlated to scores for eating behavior. Compared to placebo, intake of thylakoids significantly reduced hunger (21% reduction, p < 0.05), increased satiety (14% increase, p < 0.01), reduced cravings for all snacks and sweets during the day (36% reduction, p < 0.05), as well as cravings for salty (30%, p < 0.01); sweet (38%, p < 0.001); and sweet-and-fat (36%, p < 0.05) snacks, respectively, and decreased subjective liking for sweet (28% reduction, p < 0.01). The treatment effects on wanting all snacks, sweet-and-fat snacks in particular, were positively correlated to higher emotional eating scores (p < 0.01). The treatment effect of thylakoids on scores for wanting and liking were correlated to a reduced intake by treatment (p < 0.01 respectively), even though food intake was not affected significantly. In conclusion, thylakoids may be used as a food supplement to reduce hedonic hunger, associated with overeating and obesity. Individuals scoring higher for emotional eating behavior may have enhanced treatment effect on cravings for palatable food

The additive effect of allopregnanolone on ghrelin's orexigenic effect in rats

The progesterone metabolite, allopregnanolone (AlloP), is a GABAA receptor modulating steroid and is known to have orexigenic and pro-obesity effects. The neurobiological mechanisms underpinning these effects are most likely due to enhanced GABAergic signaling in the lateral arcuate nucleus (ARC) and medial paraventricular nucleus (PVN) of the hypothalamus. Inspired by the finding that GABAergic signaling is also important for the orexigenic effects of the circulating hormone, ghrelin, we sought to determine the extent to which AlloP (one of the most potent endogenous GABAA-receptor modulators) operates alongside ghrelin to enhance food intake. Male rats with ad libitum access to standard chow were injected intravenously with AlloP and/or ghrelin, alone or in combination. The intake of the standard chow was greater after AlloP 1 mg/kg together with ghrelin 30 μg/kg than with 30 μg/kg ghrelin alone. Food intake was also increased for the combined treatment of AlloP 0.5 mg/kg + ghrelin 10 μg/kg, AlloP 1 mg/kg + ghrelin 10 μg/kg, and AlloP 0.5 mg/kg + ghrelin 30 μg/kg. There was no significant difference in food intake between the two ghrelin doses or between the two doses of AlloP and the vehicle. In electrophysiological studies, physiologically relevant concentrations of AlloP prolonged the current decay time of spontaneous inhibitory post-synaptic current of dissociated cells of the ARC and PVN. We conclude that AlloP enhances the hyperphagic effect of ghrelin, findings of potential relevance for the hyperphagia associated with the luteal phase of the reproductive cycle

Exendin-4 attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice.

<p>(A) Nicotine-induced (0.5 mg/kg IP) locomotor stimulation was attenuated by a single injection of Ex4 (2.4 μg/kg IP) (n=8 in each group; **<i>P</i><0.01 and ***<i>P</i><0.001, one-way ANOVA followed by a Bonferroni post-hoc test). (B) First we demonstrated a significant effect of nicotine (0.5 mg/kg IP) to increase dopamine release in comparison to vehicle treatment at time intervals 40-180 minutes (**P<0.01, ***P<0.01, veh-nic compared to veh-veh treatment). Secondly we showed that pre-treatment with Ex4 (2.4 μg/kg IP) attenuated the nicotine-induced increase in dopamine release compared to vehicle pre-treatment at time interval 40-60 and 100-180 minutes (+<0.05, ++P<0.01, +++P<0.01, Ex4-nic compared to veh-nic treatment). There was no difference in response between the veh-veh and Ex4-nic groups at a dose of Ex4 that had no effect <i>per </i><i>se</i>. Arrows represent time points of injection of Ex4, vehicle and nicotine. Data analyzed with a Two-way ANOVA followed by a Bonferroni post-hoc test (n=8 in each group) (C) The nicotine-induced (0.5 m/kg IP) condition place preference (CPP) was attenuated by an acute single IP injection of Ex4 (2.4 μg/kg IP) in mice (n=8 in each group, *<i>P</i><0.05, unpaired t-test). All values represent mean ± SEM. Arrow shows time for injections. </p