| 1. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Hedonic and incentive signals for body weight control.
- 2011
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Ingår i: Reviews in endocrine & metabolic disorders. - : Springer Science and Business Media LLC. - 1573-2606 .- 1389-9155. ; 12:3, s. 141-51
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 2. |
- Skibicka, Karolina P, et al.
(författare)
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Ghrelin directly targets the ventral tegmental area to increase food motivation.
- 2011
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 180, s. 129-37
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Tidskriftsartikel (refereegranskat)abstract
- Ghrelin, a circulating orexigenic stomach-derived hormone, has recently been implicated in extra-homeostatic feeding, increasing food reward and food-motivated behavior. The precise target site(s) for ghrelin's effects on food reward have yet to be elucidated. The neurocircuitry underpinning food-motivated behavior involves, in particular, the dopamine cells of the ventral tegmental area (VTA) that project to the nucleus accumbens (NAcc). Ghrelin stimulation in both of these mesolimbic reward areas increases chow intake. Here we sought to determine if ghrelin acts directly within these mesolimbic reward areas to increase food reward/motivation in studies that combine feeding behavior, pharmacology, and neuroanatomy. We found that motivated behavior for a sucrose reward, assessed in an operant conditioning paradigm in rats, was increased when ghrelin was microinjected directly into the VTA but not into the NAcc. By contrast, ghrelin administration to both areas increased the free feeding of chow. Importantly, in a state of overnight food restriction, where endogenous levels of ghrelin are increased, ghrelin receptor (GHS-R1A) blockade in the VTA was sufficient to decrease the motivation to work for a sugar reward. Blockade of the GHS-R1A in VTA or NAcc was not sufficient to reduce fasting-induced chow hyperphagia. Taken together our data identify the VTA but not the NAcc as a direct, necessary, and sufficient target site for ghrelin's action on food motivation.
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| 3. |
- Alvarez-Crespo, Mayte, 1980, et al.
(författare)
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The Amygdala as a Neurobiological Target for Ghrelin in Rats: Neuroanatomical, Electrophysiological and Behavioral Evidence
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Here, we sought to demonstrate that the orexigenic circulating hormone, ghrelin, is able to exert neurobiological effects (including those linked to feeding control) at the level of the amygdala, involving neuroanatomical, electrophysiological and behavioural studies. We found that ghrelin receptors (GHS-R) are densely expressed in several subnuclei of the amygdala, notably in ventrolateral (LaVL) and ventromedial (LaVM) parts of the lateral amygdaloid nucleus. Using whole-cell patch clamp electrophysiology to record from cells in the lateral amygdaloid nucleus, we found that ghrelin reduced the frequency of mEPSCs recorded from large pyramidal-like neurons, an effect that could be blocked by co-application of a ghrelin receptor antagonist. In ad libitum fed rats, intra-amygdala administration of ghrelin produced a large orexigenic response that lasted throughout the 4 hr of testing. Conversely, in hungry, fasted rats ghrelin receptor blockade in the amygdala significantly reduced food intake. Finally, we investigated a possible interaction between ghrelin's effects on feeding control and emotional reactivity exerted at the level of the amygdala. In rats allowed to feed during a 1-hour period between ghrelin injection and anxiety testing (elevated plus maze and open field), intra-amygdala ghrelin had no effect on anxiety-like behavior. By contrast, if the rats were not given access to food during this 1-hour period, a decrease in anxiety-like behavior was observed in both tests. Collectively, these data indicate that the amygdala is a valid target brain area for ghrelin where its neurobiological effects are important for food intake and for the suppression of emotional (anxiety-like) behaviors if food is not available.
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| 4. |
- Anderberg, Rozita H, 1976, et al.
(författare)
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Dopamine signaling in the amygdala, increased by food ingestion and GLP-1, regulates feeding behavior.
- 2014
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Ingår i: Physiology & behavior. - : Elsevier BV. - 1873-507X .- 0031-9384. ; 136, s. 135-144
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Tidskriftsartikel (refereegranskat)abstract
- Mesolimbic dopamine plays a critical role in food-related reward processing and learning. The literature focuses primarily on the nucleus accumbens as the key dopaminergic target in which enhanced dopamine signaling is associated with reward. Here, we demonstrate a novel neurobiological mechanism by which dopamine transmission in the amygdala regulates food intake and reward. We show that food intake was associated with increased dopamine turnover in the amygdala. Next, we assess the impact of direct intra-amygdala D1 and D2 receptor activation on food intake and sucrose-driven progressive ratio operant conditioning in rats. Amygdala D2 receptor activation reduced food intake and operant behavior for sucrose, whereas D2 receptor blockade increased food intake but surprisingly reduced operant behavior. In contrast, D1 receptor stimulation or blockade did not alter feeding or operant conditioning for food. The glucagon-like peptide 1 (GLP-1) system, a target for type 2 diabetes treatment, in addition to regulating glucose homeostasis, also reduces food intake. We found that central GLP-1R receptor activation is associated with elevated dopamine turnover in the amygdala, and that part of the anorexic effect of GLP-1 is mediated by D2 receptor signaling in the amygdala. Our findings indicate that amygdala dopamine signaling is activated by both food intake and the anorexic brain-gut peptide GLP-1 and that amygdala D2 receptor activation is necessary and sufficient to change feeding behavior. Collectively these studies indicate a novel mechanism by which the dopamine system affects feeding-oriented behavior at the level of the amygdala.
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| 5. |
- Cardona Cano, Sebastian, et al.
(författare)
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Role of ghrelin in the pathophysiology of eating disorders: Implications for pharmacotherapy
- 2012
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Ingår i: CNS Drugs. - : Springer Science and Business Media LLC. - 1172-7047 .- 1179-1934. ; 26, s. 281-296
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Forskningsöversikt (refereegranskat)abstract
- Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gut-brain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader-Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs. © 2012 Adis Data Information BV. All rights reserved.
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| 6. |
- Dickson, Suzanne L., 1966, et al.
(författare)
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Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents.
- 2010
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 171:4, s. 1180-1186
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Tidskriftsartikel (refereegranskat)abstract
- Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotinic cholinergic receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc), partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine but not by hexamethonium, a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A (GHS-R1A), was found to co-localize with choline acetyltransferase (ChAT), a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine i.p. treatment decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food.
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| 7. |
- Dickson, Suzanne L., 1966, et al.
(författare)
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Enteroendocrine hormones-central effects on behavior
- 2013
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Ingår i: Current opinion in pharmacology. - : Elsevier BV. - 1471-4892 .- 1471-4973. ; 13:6, s. 977-982
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Tidskriftsartikel (refereegranskat)abstract
- A number of appetite-regulating gut hormones alter behaviors linked to reward, anxiety/mood, memory and cognitive function, although for some of these (notably GLP-1 and CCK) the endogenous signal may be CNS-derived. From a physiological perspective it seems likely that these hormones, whose secretion is altered by nutritional status and by bariatric weight loss surgery, orchestrate neurobiological effects that are integrated and linked to feeding/metabolic control. Consistent with a role in hunger and meal initiation, ghrelin increases motivated behavior for food and, when food is not readily available, decreases behaviors in anxiety tests that would otherwise hinder the animal from finding food. Of the many anorexigenic signals, GLP-1 and PYY have been linked to a suppressed reward function and CCK (and possibly GLP-1) to increased anxiety-like behavior.
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| 8. |
- Dickson, Suzanne L., 1966, et al.
(författare)
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The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors.
- 2012
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:14, s. 4812-20
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Tidskriftsartikel (refereegranskat)abstract
- The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.
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| 9. |
- Dickson, Suzanne L., 1966, et al.
(författare)
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The role of the central ghrelin system in reward from food and chemical drugs.
- 2011
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Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 340:1, s. 80-87
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Forskningsöversikt (refereegranskat)abstract
- Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link". This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the "cholinergic-dopaminergic" reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour ("wanting" or "incentive motivation"). Further, direct injection of ghrelin into the brain ventricles or into the VTA increases the consumption of rewarding foods as well as alcohol in mice and rats. Studies in rodents show beneficial effects of ghrelin receptor (GHS-R1A) antagonists to suppress the intake of palatable food, to reduce preference for caloric foods, to suppress food reward and motivated behaviour for food. They have also been shown to reduce alcohol consumption, suppress reward induced by alcohol, cocaine and amphetamine. Furthermore, variations in the GHS-R1A and pro-ghrelin genes have been associated with high alcohol consumption, smoking and increased weight gain in alcohol dependent individuals as well as with bulimia nervosa and obesity. Thus, the central ghrelin signalling system interfaces neurobiological circuits involved in reward from food as well as chemical drugs; agents that directly or indirectly suppress this system emerge as potential candidate drugs for suppressing problematic over-eating that leads to obesity as well as for the treatment of substance use disorder.
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| 10. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Ghrelin increases intake of rewarding food in rodents
- 2010
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 15:3, s. 304-311
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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