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Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite
Open accessAbstract
The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.
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“neurons in the VTA and/or NAc express GLP-1 (24,25), ghrelin (26,27), leptin (28,29), insulin (30), orexin (31) and melanocortin receptors (32).”
From Obesity and addiction: Neurobiological overlaps (2013) · cites this paper as [26]
In the citing paper
“Moreover, neurons in VTA and/or nucleus accumbens (NAc) express glucagon-like peptide-1 (11,12), ghrelin (13,14), leptin (15,16), insulin (17), orexin (18), and melanocortin receptors (19).”
From The Addictive Dimensionality of Obesity (2013) · cites this paper as [13]
In the citing paper
“In contrast, ghrelin action directly within the VTA appears to activate dopamine neurons, increase accumbens dopamine turnover, and increase food intake”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [1]
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Cites
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“Here, we will describe the effect of nutrient action (such as glucose and lipids) and hormones on hypothalamic ROS release, associated with peripheral metabolic regulation and food intake.”
BackgroundExpanding the definition of hypothalamic obesity
Hochberg, I., & Hochberg, Z. (2010) · Obesity Reviews · doi:10.1111/j.1467-789x.2010.00727.x · Cited by 90
“Indeed, recent studies have confirmed the specific role of neurotransmitters, including GABA (25), dopamine (26), serotonin (27), and histamine (28,29) in hypothalamic weight regulation.”
BackgroundGhrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food‐predictive stimuli
Cone, J. J., Roitman, J. D., & Roitman, M. F. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13080 · Cited by 87
“2013), including the mesolimbic system (Naleid et al. 2005; Abizaid et al. 2006; Skibicka et al. 2013).”
BackgroundGlucocorticoids, stress and eating: The mediating role of appetite‐regulating hormones
Kuckuck, S., van der Valk, E. S., Scheurink, A. J. W., van der Voorn, B., Iyer, A. M., Visser, J. A., Delhanty, P. J. D., van den Berg, S. A. A., & van Rossum, E. F. C. (2022) · Obesity Reviews · doi:10.1111/obr.13539 · Cited by 99
“Ghrelin is a gut peptide that is mainly produced in the stomach and acts as a potent stimulator of appetite and food intake.(10,69,70) It is”
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Growth Hormone Secretagogue Receptor Dimers: A New Pharmacological Target
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“…mechanisms, its presence in extra hypothalamic regions, including a number of limbic and midbrain structures like the ventral tegmental area (VTA), suggest that this receptor is associated in processes associated with learning and motivation (Abizaid et al., 2006; Abizaid and Horvath, 2008).”
BackgroundSelf-citationThe Role of the Ghrelin System in Drug Addiction
Zallar, L. J., Farokhnia, M., Tunstall, B. J., Vendruscolo, L. F., & Leggio, L. (2017) · International review of neurobiology · doi:10.1016/bs.irn.2017.08.002 · Cited by 87
Ghrelin Mediates Anticipation to a Palatable Meal in Rats
Merkestein, M., Brans, M. A. D., Luijendijk, M. C. M., de Jong, J. W., Egecioglu, E., Dickson, S. L., & Adan, R. A. H. (2012) · Obesity · doi:10.1038/oby.2011.389 · Cited by 95
“40), it will be interesting to discover whether ghrelin’s well-documented effects on this system (33,41) are also important for anticipatory behavior for a palatable meal.”
BackgroundValdivia, S., Cornejo, M. P., Reynaldo, M., Francesco, P. N. D., & Perelló, M. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.06.018 · Cited by 88
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“Furthermore, hormones that have been shown to change after RYGB, such as leptin and ghrelin [35,36,37], are also known to modulate the dopaminergic reward system [38,39,40,41] as well as alcohol consumption [41,42,43].”
BackgroundAMPK and the neuroendocrine regulation of appetite and energy expenditure
Stark, R., Ashley, S. E., & Andrews, Z. B. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.012 · Cited by 94
“A number of recent studies show that ghrelin acts in VTA neurons to increase food intake (Abizaid et al., 2006) and to increase the incentive value for motivated behaviors including high fat food intake (Chuang et al., 2010; Jerlhag, 2008; Perello et al., 2009, 2010; Egecioglu et al., 2010).”
Self-citationBénani, A., Hryhorczuk, C., Gouazé, A., Fioramonti, X., Brénachot, X., Guissard, C., Krezymon, A., Duparc, T., Colom, A., Nédélec, E., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0624-12.2012 · Cited by 92
“…can easily speculate that metabolic hormones, which act on the energy metabolism through their neurotrophic properties, might be involved in this physiological mechanism (Pinto et al., 2004; Abizaid et al., 2006; Coppola et al., 2007; Andrews et al., 2008; Chiu and Cline, 2010; Yang et al., 2011).”
BackgroundAnalysis of brain nuclei accessible to ghrelin present in the cerebrospinal fluid
Cabral, A., Fernandez, G., & Perello, M. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.008 · Cited by 83
“In addition, plasma ghrelin may be able to act on VTA neurons, which strongly drives motivation for food (Abizaid et al., 2006, Chuang et al., 2011).”
BackgroundBrain glucose sensing in homeostatic and hedonic regulation
Steinbusch, L. K. M., Labouèbe, G., & Thorens, B. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.06.005 · Cited by 95
Ghrelin: A link between ageing, metabolism and neurodegenerative disorders
Stoyanova, I. I. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.026 · Cited by 84
“Peripheral ghrelin injections increase spine density in the hippocampus (Berrout and Isokawa, 2012), hypothalamus (Pinto et al., 2004) and the ventral tegmental area, important for motivational aspects of multiple behaviours (Abizaid et al., 2006).”
BackgroundBrain accessibility delineates the central effects of circulating ghrelin
Perelló, M., Cabral, A., Cornejo, M. P., Francesco, P. N. D., Fernández, G., & Uriarte, M. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12677 · Cited by 83
Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin
Plasse, G., van Zessen, R., Luijendijk, M. C. M., Erkan, H., Stuber, G. D., Ramakers, G. M. J., & Adan, R. A. H. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.131 · Cited by 83
“32 ).”
Vagal Interoceptive Modulation of Motivated Behavior
Maniscalco, J. W., & Rinaman, L. (2018) · Physiology · doi:10.1152/physiol.00036.2017 · Cited by 83
“For example, operant responding for palatable food is increased in rodents after virally mediated knockdown of leptin receptor expression within the midbrain ventral tegmental area (VTA) (61), whereas administration of a ghrelin receptor antagonist into the VTA or other brain regions not only suppresses food intake an…”
BackgroundAl–Massadi, O., Nogueiras, R., Diéguez, C., & Girault, J. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.01.001 · Cited by 81
Dopamine-Based Reward Circuitry Responsivity, Genetics, and Overeating
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Dickson, S. L., Hrabovszky, E., Hansson, C., Jerlhag, E., Álvarez-Crespo, M., Skibicka, K. P., Molnar, C. S., Liposits, Z., Engel, J., & Egecioglu, E. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.10.005 · Cited by 82
“Intracerebroventricular (i.c.v.) injections of ghrelin increase accumbal dopamine levels, measured by microdialysis (Jerlhag et al., 2006) and also dopamine turnover in this area (Abizaid et al., 2006).”
InfluentialNeuroendocrine regulation of appetitive ingestive behavior
Keen‐Rhinehart, E., Ondek, K., & Schneider, J. E. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00213 · Cited by 82
“Ghrelin also appears to modulate food intake via action in the VTA, and peripheral ghrelin treatment increases DA turnover, food intake and synapses connecting with DA cells in the VTA in mice (Abizaid et al., 2006a,b).”
BackgroundLandgren, S., Engel, J. A., Hyytiä, P., Zetterberg, H., Blennow, K., & Jerlhag, E. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.03.003 · Cited by 80
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“© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction Addiction Biology, 17, 956–963 GHR induces excitation of VTA neurons (Abizaid et al. 2006) and systemic GHR injection increases dopamine overflow within the nucleus accumbens (Abizaid et al. 2006; Jerlhag 2008), and…”
BackgroundInfluentialEndogenous formaldehyde is a memory-related molecule in mice and humans
Ai, L., Tan, T., Tang, Y., Yang, J., Cui, D., Wang, R., Wang, A., Fei, X., Di, Y., Wang, X., et al. (2019) · Communications Biology · doi:10.1038/s42003-019-0694-x · Cited by 83
Dopaminergic Control of the Feeding Circuit
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“For example, it has been demonstrated that leptin and insulin inhibit VTA dopamine neurons, while ghrelin activates them [11-17].”
BackgroundGastric bypass surgery for treatment of hypothalamic obesity after craniopharyngioma therapy
Inge, T. H., Pfluger, P. T., Zeller, M. H., Rose, S. R., Burget, L., Sundararajan, S., Daniels, S. R., & Tschöp, M. H. (2007) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0579 · Cited by 80
Self-citationStress and obesity: The ghrelin connection
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Self-citationDysregulation of the Mesolimbic Dopamine System and Reward in MCH−/− Mice
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Ghrelin regulates gastric phase III‐like contractions in freely moving conscious mice
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“Doublelabeling studies in rats and mice have demonstrated both pre- and post synaptic GHSR-1A in the VTA (Abizaid et al., 2006).”
BackgroundMethodInfluentialG Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor
Evron, T., Peterson, S. M., Urs, N. M., Bai, Y., Rochelle, L. K., Caron, M. G., & Barak, L. S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.581397 · Cited by 75
Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward autoactivation loop in mice
Varela, L., Stutz, B., Song, J. E., Kim, J. G., Liu, Z.-W., Gao, X., & Horváth, T. L. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144239 · Cited by 75
“Gating of neuronal perikarya by inhibitory inputs is crucial for filtering excitation-evoked firing of effector neurons, such as the principal neurons of the cortex and hippocampus (5, 42–45).”
Self-citationNicotinic Regulation of Energy Homeostasis
Zoli, M., & Picciotto, M. R. (2012) · Nicotine & Tobacco Research · doi:10.1093/ntr/nts159 · Cited by 76
Self-citationLinking Stress and Infertility: A Novel Role for Ghrelin
Sominsky, L., Hodgson, D. M., McLaughlin, E. A., Smith, R., Wall, H. M., & Spencer, S. J. (2017) · Endocrine Reviews · doi:10.1210/er.2016-1133 · Cited by 79
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Self-citationThe Ghrelin Signalling System Is Involved in the Consumption of Sweets
Landgren, S., Simms, J. A., Thelle, D. S., Strandhagen, E., Bartlett, S. E., Engel, J. A., & Jerlhag, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018170 · Cited by 75
“The gastric-derived orexigenic peptide, ghrelin [7], affects brain circuits involved in energy balance [8] as well as in reward [9,10].”
BackgroundGhrelin and Neurodegenerative Disorders—a Review
Shi, L.-M., Du, X.-X., Jiang, H., & Xie, J.-X. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9729-1 · Cited by 73
Rossi, M. A., Basiri, M. L., Liu, Y., Hashikawa, Y., Hashikawa, K., Fenno, L. E., Kim, Y. S., Ramakrishnan, C., Deisseroth, K. A., & Stuber, G. D. (2021) · Neuron · doi:10.1016/j.neuron.2021.09.020 · Cited by 73
Neurobiology Driving Hyperactivity in Activity-Based Anorexia
Adan, R. A. H., Hillebrand, J. J., Danner, U. N., Cano, S. C., Kas, M. J., & Verhagen, L. A. W. (2010) · Current topics in behavioral neurosciences · doi:10.1007/7854_2010_77 · Cited by 75
Disruption of cue-potentiated feeding in mice with blocked ghrelin signaling
Walker, A. K., Ibia, I. E., & Zigman, J. M. (2012) · Physiology & Behavior · doi:10.1016/j.physbeh.2012.10.003 · Cited by 74
“GHSR levels in BLA brain punches were on par with those in the VTA, which is a region well-characterized for GHSR expression, while the mPFC displayed a lack of significant GHSR expression, confirming previous reports [18, 28, 30] (Figure 6A).”
ResultMultiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells
Chung, H., Li, E., Kim, Y., Kim, S., & Park, S. (2013) · Journal of Endocrinology · doi:10.1530/joe-13-0045 · Cited by 74
“…and memory (Diano et al. 2006), anxiety and depression (Carlini et al. 2004, Lutter et al. 2008), reward and motivation (Naleid et al. 2005, Abizaid et al. 2006, Jiang et al. 2006), and neuroprotection (Jiang et al. 2006, 2008, Chung et al. 2007, Miao et al. 2007, Hwang et al. 2009, Moon…”
BackgroundGhrelin Regulation of Glucose Metabolism
Gray, S., Page, L. C., & Tong, J. (2019) · Journal of neuroendocrinology · doi:10.1111/jne.12705 · Cited by 45
Neuronal Deletion of Ghrelin Receptor Almost Completely Prevents Diet-Induced Obesity
Lee, J. H., Lin, L., Xu, P., Saito, K., Wei, Q., Meadows, A. G., Bongmba, O. Y. N., Pradhan, G., Zheng, H., Xu, Y., et al. (2016) · Diabetes · doi:10.2337/db15-1587 · Cited by 73
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“Various mechanisms influence reward in relation to food, among these are gut appetite hormones, such as ghrelin (Abizaid et al., 2006; Egecioglu et al., 2010; Jerlhag et al., 2006; Merkestein et al., 2012; Skibicka, Hansson, Egecioglu, & Dickson, 2012) and GLP-1 ( Alhadeff, Rupprecht, & Hayes, 2012;…”
BackgroundInfluence of ghrelin on the central serotonergic signaling system in mice
Hansson, C., Álvarez-Crespo, M., Taube, M., Skibicka, K. P., Schmidt, L., Karlsson-Lindahl, L., Egecioglu, E., Nissbrandt, H., & Dickson, S. L. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.12.012 · Cited by 72
“, 1988), and dopamine cells in this region are known to express GHS-R1A and be ghrelin responsive (Abizaid et al., 2006).”
Ghrelin: Central and Peripheral Implications in Anorexia Nervosa
Méquinion, M., Langlet, F., Zgheib, S., Dickson, S. L., Dehouck, B., Chauveau, C., & Viltart, O. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00015 · Cited by 83
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Reduced locomotor responses to cocaine in ghrelin-deficient mice
Abizaid, A. B., Mineur, Y. S., Roth, R. H., Elsworth, J. D., Sleeman, M., Picciotto, M. R., & Horváth, T. L. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.06.001 · Cited by 72
“Ghrelin receptors in the VTA are predominantly localized to dopaminergic neurons, and direct application of ghrelin onto these cells increases their firing frequency through an increase in presynaptic excitatory neurotransmission (Abizaid et al., 2006).”
BackgroundResultInfluentialSelf-citationPristerà, A., Lin, W., Kaufmann, A.-K., Brimblecombe, K. R., Threlfell, S., Dodson, P. D., Magill, P. J., Fernandes, C., Cragg, S. J., & Ang, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1503911112 · Cited by 73
“Another interesting possibility is that FOXA1/2 mutant mice fail to appropriately integrate signaling arising from the action of orexigenic peptides (60) and/or inputs from brain centers regulating feeding (61, 62), thus failing to sense the physiological energetic state.”
BackgroundFeeding circuit development and early-life influences on future feeding behaviour
Zeltser, L. M. (2018) · Nature reviews. Neuroscience · doi:10.1038/nrn.2018.23 · Cited by 74
van Zessen, R., Plasse, G., & Adan, R. A. H. (2012) · Proceedings of The Nutrition Society · doi:10.1017/s0029665112000614 · Cited by 72
“Finally, ghrelin deficient and GHSR knock out animals do not increase their food intake over days when they are food restricted overnight((66)).”
InfluentialThe central nervous system at the core of the regulation of energy homeostasis
Magnan, C. (2009) · Frontiers in Bioscience-Scholar · doi:10.2741/s37 · Cited by 73
“in the VTA, where direct infusion induced robust feeding (110) and promotes synaptic re-organization together with striatal dopamine release (111).”
Mesolimbic dopamine and its neuromodulators in obesity and binge eating
Naef, L., Pitman, K. A., & Borgland, S. L. (2015) · CNS Spectrums · doi:10.1017/s1092852915000693 · Cited by 70
Designing for action: an evaluation of social recipes in reducing food waste
Lim, V., Funk, M., Marcenaro, L., Regazzoni, C., & Rauterberg, M. (2017) · International Journal of Human-Computer Studies · doi:10.1016/j.ijhcs.2016.12.005 · Cited by 69
“Factors influencing food waste behavior Starting from our biological inclination, every time we smell food, dopamine is released to increase appetite (Abizaid et al., 2006): when we smell food while passing by food stands, we might experience difficulty to resist food.”
BackgroundEnteroendocrine hormones – central effects on behavior
Skibicka, K. P., & Dickson, S. L. (2013) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2013.09.004 · Cited by 69
The Role of Ghrelin in Regulating Synaptic Function and Plasticity of Feeding-Associated Circuits
Serrenho, D., Santos, S. D., & Carvalho, A. L. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00205 · Cited by 69
Novak, C. M., & Levine, J. A. (2007) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01606.x · Cited by 74
Kampe, J., Tschöp, M. H., Hollis, J. H., & Oldfield, B. J. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06818.x · Cited by 69
“Interestingly, the adipocyte-derived hormone leptin and the gutderived hormones ghrelin (Abizaid et al., 2006; Malik et al., 2008) and peptide YY (Batterham et al., 2007) are likely to act locally to influence the activity of this mesolimbic pathway.”
BackgroundSelf-citationLong-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats
Strassburg, S., Anker, S. D., Castañeda, T. R., Burget, L., Pérez–Tilve, D., Pfluger, P. T., Nogueiras, R., Halem, H. A., Dong, J. Z., Culler, M. D., et al. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00040.2008 · Cited by 69
“Although it can be assumed that the orexigenic effects of the tested ghrelin agonists may, similar to ghrelin, be mediated via stimulation of hypothalamic NPY/AgRP neurons and midbrain reward circuitry (1), their exact mechanism of action has yet to be proven.”
Self-citationEdwards, A., & Abizaid, A. B. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040859 · Cited by 71
“Ghrelin activates these VTA dopamine eurons both directly by binding to GHSR rec ptors located on their surface and indirectly by increasing the ratio of excitatory to i hibitor synapses contacting them.”
BackgroundInfluentialSelf-citationHigh-fat diet exacerbates cognitive rigidity and social deficiency in the BTBR mouse model of autism
Zilkha, N., Kuperman, Y., & Kimchi, T. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.01.070 · Cited by 72
“…the prefrontal cortex (Vucetic et al., 2012; Grissom et al., 2015), nucleus accumbens (South and Huang, 2008; Labouesse et al., 2013), ventral tegmental area (Abizaid et al., 2006) (Teegarden et al., 2008) and the hypothalamus (Li et al., 2009; Vucetic et al., 2012; Kaczmarczyk et al., 2013).”
GOAT induced ghrelin acylation regulates hedonic feeding
Davis, J. F., Perelló, M., Choi, D. L., Magrisso, I. J., Kirchner, H., Pfluger, P. T., Tschoep, M. H., Zigman, J. M., & Benoit, S. C. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.08.009 · Cited by 68
Insulin and ghrelin: peripheral hormones modulating memory and hippocampal function
McNay, E. C. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.10.009 · Cited by 67
Functional Organization of Neuronal and Humoral Signals Regulating Feeding Behavior
Schwartz, G. J., & Zeltser, L. M. (2013) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161125 · Cited by 67
“VTA injections of ghrelin can stimulate food reward behavior and extracellular dopamine concentration in the NAc; these effects are likely mediated via VTA to NAc projections, as direct injections into the NAc do not affect feeding behavior (1, 59, 110).”
Many mouths to feed: The control of food intake during lactation
Woodside, B. C., Budin, R., Wellman, M. K., & Abizaid, A. B. (2012) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2012.09.002 · Cited by 67
“…aminergic groups in regulating energy balance has recently been reconsidered in light of evidence that they are sensitive to direct stimulation by metabolic hormones and substrates like glucose (Abizaid et al., 2006; Fulton et al., 2006; Hommel et al., 2006; Levin, 2000; Orosco et al., 1991).”
BackgroundInfluentialSelf-citationAlcohol misuse after bariatric surgery: epiphenomenon or “Oprah” phenomenon?
Sogg, S. (2007) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2007.03.004 · Cited by 66
Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala
Jensen, M. G., Ratner, C., Rudenko, O., Christiansen, S. H., Skov, L. J., Hundahl, C., Woldbye, D. P. D., & Holst, B. (2015) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyv123 · Cited by 66
“Ghrelin has been shown to increase food intake when injected into discrete brain regions, including the hypothalamus, hippocampus, and ventral tegmental area (Olszewski et al., 2003; Carlini et al., 2004; Abizaid et al., 2006).”
Cornejo, M. P., Castrogiovanni, D. C., Schiöth, H. B., Reynaldo, M. B., Marie, J., Fehrentz, J., & Perelló, M. (2019) · Journal of Neuroendocrinology · doi:10.1111/jne.12785 · Cited by 66
Thompson, J. L., & Borgland, S. L. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.10.026 · Cited by 65
The role of ghrelin in addiction: a review
Panagopoulos, V. N., & Ralevski, E. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3640-0 · Cited by 66
Atalayer, D., Gibson, C. D., Konopacka, A., & Geliebter, A. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.08.011 · Cited by 65
Centrally Administered Ghrelin Acutely Influences Food Choice in Rodents
Schéle, E., Bake, T., Rabasa, C., & Dickson, S. L. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149456 · Cited by 65
“Previous studies have shown that ghrelin activates this projection: (1) ghrelin causes NAcc dopamine release [27], activates VTA neurons [28] and that VTA delivery of ghrelin induces food intake [10, 29] and increases motivation for sucrose food rewards [14], effects involving D1/D2 dopamine signaling in the NAcc [16].”
BackgroundSivertsen, B., Holliday, N. D., Madsen, A. N., & Holst, B. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12361 · Cited by 68
“This effect was reversed by infusion of a ghrelin receptor antagonist into the VTA, which reduced ghrelin-induced feeding behaviour (Abizaid et al., 2006).”
BackgroundFood reward functions as affected by obesity and bariatric surgery
Shin, A. C., & Berthoud, H. R. (2011) · International Journal of Obesity · doi:10.1038/ijo.2011.147 · Cited by 68
Ghrelin, Reward and Motivation
Menzies, J. R. W., Skibicka, K. P., Leng, G., & Dickson, S. L. (2013) · Endocrine development · doi:10.1159/000346058 · Cited by 64
Engel, J. A., Nylander, I., & Jerlhag, E. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.10.004 · Cited by 64
“Supportively, GHS-R1A are located on GABAergic interneurons in the VTA (Abizaid et al., 2006).”
Marino, R. A. M., McDevitt, R. A., Gantz, S. C., Shen, H., Pignatelli, M., Xin, W., Wise, R. A., & Bonci, A. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1909340117 · Cited by 65
“Indeed, intra-VTA infusion of ghrelin or morphine at doses that increase dopamine release in terminal sites stimulates eating in sated animals (24 – 26).”
Central GLP-1 receptors: Novel molecular targets for cocaine use disorder
Hernandez, N. S., & Schmidt, H. D. (2019) · Physiology & Behavior · doi:10.1016/j.physbeh.2019.03.026 · Cited by 66
“In contrast, the feeding hormone ghrelin promotes ad libitum food intake through actions on ghrelin receptors expressed in the VTA and nucleus accumbens [76, 77].”
BackgroundHolsen, L. M., Lawson, E. A., Christensen, K. A., Klibanski, A., & Goldstein, J. M. (2014) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2014.04.015 · Cited by 63
“…are in line with findings from studies demonstrating activation of the amygdala (Malik et al., 2008), insula (Malik et al., 2008), and OFC (Malik et al., 2008) following peripheral administration of ghrelin in humans (Malik et al., 2008) and animals (Abizaid et al., 2006; Jerlhag et al., 2006).”
ResultTargeting the ghrelin receptor to regulate food intake
Depoortere, I. (2009) · Regulatory Peptides · doi:10.1016/j.regpep.2009.04.002 · Cited by 64
Midbrain response to milkshake correlates with ad libitum milkshake intake in the absence of hunger
Nolan-Poupart, S., Veldhuizen, M. G., Geha, P., & Small, D. M. (2012) · Appetite · doi:10.1016/j.appet.2012.09.032 · Cited by 63
“$w aterm ark-text $w aterm ark-text $w aterm ark-text like the ventral tegmental dopamine neurons (Abizaid et al., 2006a; Berthoud, 2002) are directly modulated by hormones to promote eating is unknown.”
BackgroundGhrelin and eating behavior: evidence and insights from genetically-modified mouse models
Uchida, A., Zigman, J. M., & Perelló, M. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00121 · Cited by 62
Albarran-Zeckler, R. G., Brantley, A. F., & Smith, R. G. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.03.012 · Cited by 64
“These results were surprising because Abizaid et al showed that ghrelin has been shown to improve memory in rodents [4] and, ghsr−/− mice showed deficits in water maze in separate studies performed in different line of ghsr−/− mice [37] [38].”
ResultReichelt, A. C., Westbrook, R. F., & Morris, M. J. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13321 · Cited by 62
“Ghrelin controls motivation to eat via its interaction with the mesolimbic dopamine circuitry (Abizaid et al., 2006; Overduin et al., 2012), while leaving the hedonic value of the food eaten unaffected, as measured by analysis of licking microstructure (initial lick rates or lick-cluster size)…”
BackgroundSystematic review of the effects of acute stress in binge eating disorder
Naish, K. R., Laliberte, M. M., MacKillop, J. M., & Balodis, I. M. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14110 · Cited by 70
“Indeed, high levels of ghrelin receptors are found in the VTA (Guan et al., 1997; Zigman et al., 2006), and administering ghrelin to the VTA increases dopamine turnover in the nucleus accumbens (Abizaid et al., 2006).”
BackgroundCornejo, M. P., Barrile, F., Francesco, P. N. D., Portiansky, E. L., Reynaldo, M., & Perelló, M. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.09.027 · Cited by 63
The neurological effects of ghrelin in brain diseases: Beyond metabolic functions
Jiao, Q., Du, X., Li, Y., Gong, B., Shi, L., Tang, T., & Jiang, H. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.12.010 · Cited by 62
Kawahara, Y., Kawahara, H., Kaneko, F., Yamada, M., Nishi, Y., Tanaka, E., & Nishi, A. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.03.086 · Cited by 61
Hindbrain Ghrelin Receptor Signaling Is Sufficient to Maintain Fasting Glucose
Scott, M. M., Perelló, M., Chuang, J.-C., Sakata, I., Gautron, L., Lee, C. E., Lauzon, D. A., Elmquist, J. K., & Zigman, J. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044089 · Cited by 61
“Increased food intake also occurs upon ghrelin injection into the ventral tegmental area (VTA) of the midbrain [18,19], an effect lost in the ghrelin receptor null animals.”
BackgroundSuda, Y., Kuzumaki, N., Sone, T., Narita, M., Tanaka, K., Hamada, Y., Iwasawa, C., Shibasaki, M., Maekawa, A., Matsuo, M., et al. (2018) · Molecular Brain · doi:10.1186/s13041-018-0349-8 · Cited by 60
“thalamus, ventral tegmental area and hippocampus, where ghrelin directly modulates neuronal activity [6, 7, 11, 12].”
Farhadipour, M., & Depoortere, I. (2021) · Nutrients · doi:10.3390/nu13061839 · Cited by 65
The influence of leptin on the dopamine system and implications for ingestive behavior
Dileone, R. (2009) · International Journal of Obesity · doi:10.1038/ijo.2009.68 · Cited by 60
Raspopow, K., Matheson, K., Abizaid, A. B., & Anisman, H. (2012) · Appetite · doi:10.1016/j.appet.2012.11.031 · Cited by 70
Self-citationGhrelin in Alzheimer’s disease: Pathologic roles and therapeutic implications
Jeon, S. G., Hong, S. B., Nam, Y., Tae, J., Yoo, A., Song, E. J., Kim, K. I., Lee, D., Park, J., Lee, S. M., et al. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100945 · Cited by 60
Diet-induced obesity causes ghrelin resistance in reward processing tasks
Lockie, S. H., Dinan, T., Lawrence, A. J., Spencer, S. J., & Andrews, Z. B. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.08.004 · Cited by 58
“Intra-VTA delivery of ghrelin increases feeding and operant responding for sucrose in chow fed animals, showing that ghrelin targets VTA dopamine neurons to increase food intake (Abizaid et al., 2006; Naleid et al., 2005).”
Self-citation
Metadata
- Authors
- Abizaid, A., Liu, Z.-W., Andrews, Z. B., Shanabrough, M., Borok, E., Elsworth, J. D., Roth, R. H., Sleeman, M. W., Picciotto, M. R., Tschöp, M. H., Gao, X.-B., & Horvath, T. L.
- Affiliations
- Yale University (US)
- Regeneron (United States) (US)
- University of Cincinnati (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2006-12-01
- Volume
- 116
- Issue
- 12
- Pages
- 3229-3239
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2086950122
- Cited by
- 984
- References
- 58
- Citations by year
- 2026: 23 · 2025: 33 · 2024: 31 · 2023: 34 · 2022: 46 · 2021: 53 · 2020: 44 · 2019: 40 · 2018: 56 · 2017: 66 · 2016: 51 · 2015: 57 · 2014: 60 · 2013: 73 · 2012: 78
- FWCI
- 15.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- Ipsen
- National Institutes of Health (5r01mh057483-13, DK056863)
- Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, Yale University
- National Institute on Alcohol Abuse and Alcoholism (P50AA015632)
- National Institute on Aging (R01AG022880, AG-022880)
- National Institute of Mental Health (R01-MH057483, R01MH014092, MH014092, MH057483, R37MH014092)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK070723, DK-056863, DK-069987, DK 060711, DK 070723, P01DK056863, DK074386, R01DK069987, R01DK074386, R01DK060711)
- National Institute of Neurological Disorders and Stroke (R01NS041725, NS-041725)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- ghrelin, ventral tegmental area, dopaminergic neurons, nucleus accumbens, synaptic plasticity, feeding behavior, appetite, mesolimbic reward circuitry, energy metabolism
- MeSH terms
- Action Potentials, Animals, Appetite, Dopamine, Fluorescent Antibody Technique, Male, Mesencephalon, Mice, Inbred C57BL, Neurons, Nucleus Accumbens, Time Factors, Rats, Sprague-Dawley, Ventral Tegmental Area, Mice, Knockout, Patch-Clamp Techniques, Peptide Hormones, Receptors, G-Protein-Coupled, Mice, Rats, Ghrelin, Receptors, Ghrelin
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