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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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“More recently, several studies have demonstrated the importance of ghrelin and the ghrelin receptor in reward-associated circuits (Abizaid et al. 2006; Jerlhag et al. 2006; and for review, see Dickson et al. 2011).”
BackgroundGhrelin and LEAP-2: Rivals in Energy Metabolism
Al–Massadi, O., Müller, T. D., Tschöp, M. H., Diéguez, C., & Nogueiras, R. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.06.004 · Cited by 59
Self-citationCRISPR System: A High-throughput Toolbox for Research and Treatment of Parkinson’s Disease
Safari, F., Hatam, G., Behzad‐Behbahani, A., Tabar, V. R., Barekati‐Mowahed, M., Petramfar, P., & Khademi, F. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00761-w · Cited by 66
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InfluentialOliveira-Maia, A. J., Roberts, C. D., Walker, Q. D., Luo, B., Kuhn, C. M., Simon, S. A., & Nicolelis, M. A. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024992 · Cited by 58
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Mietus‐Snyder, M., & Lustig, R. H. (2007) · Annual Review of Medicine · doi:10.1146/annurev.med.59.103106.105628 · Cited by 58
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“Nesfatin-1 effect on VTA seems to analogous to the leptin but different than ghrelin action (Hommel et al. 2006, Abizaid et al. 2006) It can be therefore possible that nesfatin-1 neurons in the lateral amygdala send their inhibitory efferents to the VTA neurons that evoke the anorexigenic effect.”
Hamamah, S., Hajnal, A. S., & Covașă, M. (2024) · Nutrients · doi:10.3390/nu16071071 · Cited by 65
“For example, ghrelin alters dopaminergic receptor expression by acting on its receptor, GHSR1a, in the VTA and nucleus accumbens [242].”
BackgroundDifferential effects of chronic social stress and fluoxetine on meal patterns in mice
Kumar, J., Chuang, J.-C., Na, E. S., Kuperman, A., Gillman, A. G., Mukherjee, S., Zigman, J. M., McClung, C. A., & Lutter, M. L. (2013) · Appetite · doi:10.1016/j.appet.2012.12.023 · Cited by 58
“Interestingly, ghrelin receptors expressed on presynaptic dopaminergic neurons of the VTA are known to provide excitatory input to this neuronal population (Abizaid et al., 2006), and infusion of ghrelin directly into the”
Levin, B. E. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2010.02.005 · Cited by 59
Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants
Kirchner, H., Tong, J., Tschöp, M. H., & Pfluger, P. T. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00191.2009 · Cited by 59
“Peripheral ghrelin was shown to activate dopamine receptors in the ventral tegmental area and dopamine turnover in the nucleus accumbens, thereby increasing food intake in rats (2).”
BackgroundMethodSelf-citationIntegrating GHS into the Ghrelin System
Veldhuis, J. D., & Bowers, C. Y. (2010) · International Journal of Peptides · doi:10.1155/2010/879503 · Cited by 57
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Kawahara, Y., Kaneko, F., Yamada, M., Kishikawa, Y., Kawahara, H., & Nishi, A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.022 · Cited by 57
“Activation of GHSRs in the VTA by direct application of ghrelin induces dopamine release in the NAc and feeding behavior (Jerlhag et al., 2007; Abizaid et al., 2006; Kawahara et al., 2009).”
BackgroundEffects of in utero conditions on adult feeding preferences
Portella, A. K., Kajantie, E., Hovi, P., Desai, M., Ross, M. G., Goldani, M. Z., Roseboom, T. J., & Silveira, P. P. (2012) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s2040174412000062 · Cited by 61
Understanding the role of psychopathology in bariatric surgery outcomes
Marek, R. J., Ben‐Porath, Y. S., & Heinberg, L. J. (2016) · Obesity Reviews · doi:10.1111/obr.12356 · Cited by 61
Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons
Hsu, T. M., McCutcheon, J. E., & Roitman, M. F. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00410 · Cited by 59
“Physiologically, ghrelin action in the VTA increases dopamine neuronal firing, synaptic plasticity, and NAc dopamine turnover (163).”
BackgroundGenetic Variation of the Ghrelin Signaling System in Females With Severe Alcohol Dependence
Landgren, S., Jerlhag, E., Hallman, J., Oreland, L., Lissner, L., Strandhagen, E., Thelle, D. S., Zetterberg, H., Blennow, K., & Engel, J. A. (2010) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01236.x · Cited by 56
Ghrelin in the CNS: From hunger to a rewarding and memorable meal?
Olszewski, P. K., Schiöth, H. B., & Levine, A. S. (2008) · Brain Research Reviews · doi:10.1016/j.brainresrev.2008.01.004 · Cited by 56
Ghrelin Enhances Food Odor Conditioning in Healthy Humans: An fMRI Study
Han, J. E., Frasnelli, J., Zeighami, Y., Larcher, K. M.-H., Boyle, J., McConnell, T., Malik, S., Jones‐Gotman, M., & Dagher, A. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.026 · Cited by 56
Babygirija, R., Zheng, J., Ludwig, K., & Takahashi, T. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00328.2009 · Cited by 54
Costantini, V. J. A., Vicentini, E., Sabbatini, F. M., Valerio, E., Lepore, S., Tessari, M., Sartori, M., Michielin, F., Melotto, S., Pich, E. M., et al. (2011) · Neuroendocrinology · doi:10.1159/000328968 · Cited by 55
Ghrelin and the Control of Energy Balance in Females
Smith, A., Woodside, B. C., & Abizaid, A. B. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.904754 · Cited by 55
“VTA dopaminergic neurons express the GHSR (29, 39, 40), and intra-VTA ghrelin administration in rodents results in increased DA release into NAcc as well as increasing food intake and food motivation as measured by increased lever presses for food, or in response to contextual or specific cues such as the presence of…”
BackgroundSelf-citationJerlhag, E., Ivanoff, L., Vater, A., & Engel, J. A. (2014) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.12337 · Cited by 54
“Initially, it was shown that ghrelin activates cholinergic-dopaminergic reward link (Abizaid et al., 2006; Jerlhag et al., 2006a, 2007).”
BackgroundStress, Motivation, and the Gut–Brain Axis: A Focus on the Ghrelin System and Alcohol Use Disorder
Morris, L. S., Voon, V., & Leggio, L. (2018) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13781 · Cited by 57
Glucose-Sensing in the Reward System
Koekkoek, L. L., Mul, J. D., & la Fleur, S. E. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00716 · Cited by 51
“Ghrelin, a gastric hormone that stimulates feeding, can influence both dopamine and opioid signaling (Abizaid et al., 2006; Skibicka et al., 2012).”
Brain control of energy homeostasis: implications for anti-obesity pharmacotherapy
Johansen, V. B. I., Petersen, J., Lund, J., Mathiesen, C. V., Fenselau, H., & Clemmensen, C. (2025) · Cell · doi:10.1016/j.cell.2025.06.010 · Cited by 53
Wiss, D. A., Criscitelli, K., Gold, M., & Avena, N. (2017) · Appetite · doi:10.1016/j.appet.2016.12.019 · Cited by 53
Šustková-Fišerová, M., Jerabek, P., Havlickova, T., Kačer, P., & Kršiak, M. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3466-9 · Cited by 53
“In addition to other effects, ghrelin has recently been reported to also markedly activate mesolimbic dopaminergic pathways, which is critically involved in the reinforcement circuitry of the brain’s reward system; in particular, activation of the acetylcholine-dopamine (DA) reward link in the ventral tegmental area (…”
Ghrelin inhibits LPS-induced release of IL-6 from mouse dopaminergic neurones
Beynon, A. L., Brown, M. R., Wright, R., Rees, M., Sheldon, I., & Davies, J. S. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-40 · Cited by 56
“; licensee BioMed Centra Commons Attribution License (http://creativec reproduction in any medium, provided the or [3], where it modulates the activity and synaptic organization of midbrain dopamine neurones [4].”
BackgroundFrom Disordered Eating to Addiction: The “Food Drug” in Bulimia Nervosa
Umberg, E. N., Shader, R. I., Hsu, L. K. G., & Greenblatt, D. J. (2012) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e318252464f · Cited by 52
“Ghrelin can increase NAc DA levels209,210 and increase DA neuronal activity in the VTA.211 Both central and peripheral delivery of ghrelin significantly increases the amount of work an animal is willing * 2012 Lippincott Williams & Wilkins www.psychopharmacology.com 379 Copyright © 2012 Lippincott Williams & Wilkins.”
BackgroundWoods, C. A., Guttman, Z. R., Huang, D., Kolaric, R., Rabinowitsch, A. I., Jones, K. T., de Vaca, S. C., Sclafani, A. J., & Carr, K. D. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.03.013 · Cited by 52
“Multiple studies highlight a role for various metabolic peptides in food reward, including ghrelin, (Abizaid et al., 2006; Malik et al., 2008) leptin (Davis et al., 2011; Figlewicz et al., 2004; Krügel et al., 2003), cholecystokinin (Hajnal et al., 2007), and glucagon-like peptide 1 (Dickson et…”
BackgroundMani, B. K., Osborne-Lawrence, S. L., Méquinion, M., Lawrence, S., Gautron, L., Andrews, Z. B., & Zigman, J. M. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.06.011 · Cited by 52
“Of all the actions mediated through GHSRs, one of the most robust and well-characterized is the induction of an acute feeding response after peripheral or central administration of ghrelin [3,4,36,42,46,47].”
BackgroundSelf-citationEdvardsson, C. E., Vestlund, J., & Jerlhag, E. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174039 · Cited by 52
The role of ghrelin in weight-regulation disorders: Implications in clinical practice
Solomou, S., & Korbonits, M. (2014) · HORMONES · doi:10.14310/horm.2002.1551 · Cited by 53
Picciotto, M. R. (2010) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-0346-0228-0_14 · Cited by 51
“However, both ghrelin and opiates increase feeding and are rewarding [6, 8], which means that a simple reciprocal relationship cannot explain neuropeptide effects on feeding and drug reinforcement.”
BackgroundSelf-citationPeptide YY and ghrelin predict craving and risk for relapse in abstinent smokers
Al’Absi, M., Lemieux, A. M., & Nakajima, M. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.07.018 · Cited by 51
The hormonal signature of energy deficit: Increasing the value of food reward
Lockie, S. H., & Andrews, Z. B. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.08.003 · Cited by 50
“The VTA is directly sensitive to ghrelin with direct injection of ghrelin into the VTA increasing feeding, and peripheral ghrelin injection increasing dopamine turnover in the ventral striatum [48].”
BackgroundSelf-citationReassessing wanting and liking in the study of mesolimbic influence on food intake
Nicola, S. M. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00234.2016 · Cited by 52
“Indeed, dopamine neurons are heavily regulated by signals that reflect nutrient balance: signals that typically report negative energy balance and promote appetite, such as orexin/hypocretin (45, 79, 177, 195), ghrelin (3, 45, 46, 123, 133, 204), neuropeptide Y (205), and agouti-related peptide (60), increase mesolimb…”
BackgroundActivity-based anorexia animal model: a review of the main neurobiological findings
Spadini, S., Ferro, M., Lamanna, J., & Malgaroli, A. (2021) · Journal of Eating Disorders · doi:10.1186/s40337-021-00481-x · Cited by 56
Wellman, P. J., Clifford, P. S., Rodriguez, J. A., Hughes, S., Eitan, S., Brunel, L., Fehrentz, J., & Martínez, J. (2011) · Regulatory Peptides · doi:10.1016/j.regpep.2011.08.014 · Cited by 50
“Abizaid and colleagues noted that systemic administration of GHR can reorganize VTA neurons such that these cells express more excitatory input and diminished inhibitory input [9].”
BackgroundWeinberg, Z. Y., Nicholson, M. L., & Currie, P. J. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.05.034 · Cited by 50
“[2], these findings further implicate a role for ghrelin in the mediation of reinforced behavior via the mesotelencephalic dopamine pathway.”
BackgroundGhrelin Influences Novelty Seeking Behavior in Rodents and Men
Hansson, C., Shirazi, R. H., Näslund, J., Vogel, H., Neuber, C., Holm, G., Anckarsäter, H. S., Dickson, S. L., Eriksson, E., & Skibicka, K. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050409 · Cited by 50
“For example GHSRs are located on GABAergic neurons in the VTA that regulate VTA dopamine neuron activity, and GABAergic signaling within the VTA has been implicated in novelty seeking [18].”
BackgroundSahr, A. E., Sindelar, D. K., Alexander-Chacko, J. T., Eastwood, B. J., Mitch, C. H., & Statnick, M. A. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00390.2007 · Cited by 50
Portal glucose influences the sensory, cortical and reward systems in rats
Delaere, F., Akaoka, H., Vadder, F. D., Duchampt, A., & Mithieux, G. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12354 · Cited by 61
“, 2009) or food reward (Abizaid et al., 2006; Fulton et al., 2006) involving sensory and corticolimbic areas.”
BackgroundMethodEngel, J. A., & Jerlhag, E. (2014) · Progress in brain research · doi:10.1016/b978-0-444-63425-2.00009-x · Cited by 53
Li, G., Ji, G., Hu, Y., Liu, L., Jin, Q., Zhang, W., Liu, L., Wang, Y., Zhao, J., von Deneen, K. M., et al. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.10.022 · Cited by 50
“, 2011) via activation of the mesocorticolimbic dopaminergic system (Skibicka et al., 2013; Abizaid et al., 2006).”
BackgroundKoopmann, A., Bach, P., Schuster, R., Bumb, J. M., Vollstädt‐Klein, S., Reinhard, I., Rietschel, M., Witt, S. H., Wiedemann, K., & Kiefer, F. (2018) · Addiction Biology · doi:10.1111/adb.12651 · Cited by 49
“In the ventral tegmental area (VTA), ghrelin stimulates the firing rate of dopaminergic neurons through its effects on GHS-R1A receptors (Abizaid et al. 2006).”
BackgroundNeural control of feeding behavior
Benarroch, E. E. (2010) · Neurology · doi:10.1212/wnl.0b013e3181df0a3f · Cited by 53
Hypothalamic κ-Opioid Receptor Modulates the Orexigenic Effect of Ghrelin
Romero, A., Vazquez, M. J., González-Touceda, D., Folgueira, C., Skibicka, K. P., Álvarez-Crespo, M., van Gestel, M. A., Velasquez, D., Schwarzer, C., Herzog, H., et al. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.28 · Cited by 50
“Stimulation of both KOR (Glass et al, 1999; Stanley et al, 1988) and GHS-R1A (Abizaid et al, 2006) within the VTA modulates the activity of dopamine neurons to promote appetite.”
BackgroundGómez, E. S., Bellocchio, L., & Marsicano, G. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.09.023 · Cited by 48
Ghrelin, Appetite Regulation, and Food Reward: Interaction with Chronic Stress
Diz-Chaves, Y. (2011) · International Journal of Peptides · doi:10.1155/2011/898450 · Cited by 51
“Ghrelin binds to neurons in VTA, where increases dopamine neuronal activity and dopamine turnover in the nucleus accumbens [83].”
BackgroundGhrelin is Related to Personality Differences in Reward Sensitivity and Impulsivity
Ralevski, E., Shanabrough, M., Newcomb, J., Gandelman, E. M., Hayden, R., Horváth, T. L., & Petrakis, I. L. (2017) · Alcohol and Alcoholism · doi:10.1093/alcalc/agx082 · Cited by 47
Self-citationAcylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease
Reich, N., & Hölscher, C. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.614828 · Cited by 48
“Acylated Ghrelin Induces Dopamine Transmission in the Ventral Tegmental Area and Stimulates Locomotor Activity and Memory Noteworthy, GHS-R1α was found to be expressed by ∼60% of dopaminergic neurons in the VTA of rats (Abizaid et al., 2006).”
BackgroundUriarte, M., Francesco, P. N. D., Fernández, G., Castrogiovanni, D. C., D'Arcangelo, M., Imbernón, M., Cantel, S., Denoyelle, S., Fehrentz, J., Prætorius, J., et al. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111449 · Cited by 49
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“For example, there is mounting evidence that ghrelin may enhance the hedonic appeal of foods through its action on dopaminergic reward pathways in the brain [47,48].”
BackgroundWellman, P. J., Clifford, P. S., Rodriguez, J. A., Hughes, S., Francesco, C. D., Melotto, S., Tessari, M., Corsi, M., Bifone, A., & Gozzi, A. (2011) · Addiction Biology · doi:10.1111/j.1369-1600.2011.00392.x · Cited by 47
“One explanation for this outcome is that the stimulating electrodes employed in experiment 2 were located within the medial forebrain bundle, at the level of the lateral hypothalamus, and that the ICSS of this site activated DA fibers coursing from the VTA to the NAcc.”
BackgroundInfluentialUncoupling Protein-2 Decreases the Lipogenic Actions of Ghrelin
Andrews, Z. B., Erion, D. M., Beiler, R. J., Choi, C. S., Shulman, G. I., & Horváth, T. L. (2010) · Endocrinology · doi:10.1210/en.2009-0850 · Cited by 48
“Moreover, ghrelin promotes learning and memory in the hippocampus (40), defends against depression and stress (41), and enhances reward and motivation through the mesolimbic dopamine system (42).”
BackgroundSelf-citationThe incentive salience of courtship vocalizations: Hormone-mediated ‘wanting’ in the auditory system
Maney, D. L. (2013) · Hearing Research · doi:10.1016/j.heares.2013.04.011 · Cited by 47
Early life experience alters behavioral responses to sweet food and accumbal dopamine metabolism
Silveira, P. P., Portella, A. K., Assis, S. A. C. N., Nieto, F., Diehl, L. A., Crema, L. M., Peres, W., Costa, G., Scorza, C., Quillfeldt, J. A., et al. (2009) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2009.08.018 · Cited by 53
“Acting on its receptors in the ventro- tegmental area, ghrelin enhances dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens, as well as triggers feeding (Abizaid et al., 2006; Naleid et al., 2005).”
Ghrelin-mediated appetite regulation in the central nervous system
Kirsz, K., & Zieba, D. A. (2011) · Peptides · doi:10.1016/j.peptides.2011.04.010 · Cited by 47
Ghrelin and the central regulation of feeding and energy balance
Horváth, T. L., & Abizaid, A. B. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105580 · Cited by 47
“[110-112] In line with this, we found that ghrelin has a major impact on midbrain dopamine cell function and related behaviors, including feeding and responses to cocaine.[113,114] We also showed that the other midbrain dopamine system that is localized to the SN is also targeted by ghrelin action and plays a role in…”
BackgroundSelf-citationSuchankova, P., Engel, J. A., & Jerlhag, E. (2015) · Alcohol and Alcoholism · doi:10.1093/alcalc/agv100 · Cited by 48
Edwards, A., & Abizaid, A. B. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.032 · Cited by 54
Self-citationIncontro, S., Musella, M. L., Sammari, M., Scala, C. D., Fantini, J., & Debanne, D. (2024) · Physiological Reviews · doi:10.1152/physrev.00004.2024 · Cited by 51
Haam, J., Halmos, K. C., Di, S., & Tasker, J. G. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3178-13.2014 · Cited by 46
“The GHS-R1a antibody has also been tested previously for specificity in GHSR knock-out mice (Abizaid et al., 2006).”
BackgroundMethodInfluentialFood Addiction and Neuroimaging
Zhang, Y., von Deneen, K. M., Tian, J., Gold, M. S., & Liu, Y. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795656855 · Cited by 47
“[79] Abizaid A, Liu ZW, Andrews ZB, et al.”
BackgroundDiet-Induced Obesity Attenuates Fasting-Induced Hyperphagia
Briggs, D. I., Lemus, M. B., Kua, E. H., & Andrews, Z. B. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02148.x · Cited by 46
Self-citationGhrelin and Glucagon-Like Peptide-1: A Gut-Brain Axis Battle for Food Reward
Décarie-Spain, L., & Kanoski, S. E. (2021) · Nutrients · doi:10.3390/nu13030977 · Cited by 49
“For example, VTAACB dopamine signaling is a critical for food-motivated behaviors [75], and early work from Abizaid and colleagues revealed that ghrelin binds to VTA neurons, where it increases dopamine turnover in the ACB in a GHSR-dependent manner [15].”
BackgroundResultMetabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights
Geisler, C. E., & Hayes, M. R. (2023) · Physiology & Behavior · doi:10.1016/j.physbeh.2023.114236 · Cited by 51
A talk between fat tissue, gut, pancreas and brain to control body weight
Wilson, J. L., & Enriori, P. J. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.08.022 · Cited by 39
“For example some subpopulations are activated by glucose or serotonin (Abizaid et al., 2006; Doslikova et al., 2013; Sohn et al., 2011) but not by leptin.”
Cepko, L. C. S., Selva, J. A., Merfeld, E., Fimmel, A. I., Goldberg, S. A., & Currie, P. J. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.05.030 · Cited by 45
“Ghrelin administration into the VTA increases synapse formation, dopaminergic neuronal activity and turnover, as well as operant responding for food and locomotor behavior (Abizaid et al., 2006; Jerlhag et al., 2007; Weinberg et al., 2011).”
BackgroundThe neurohormonal regulation of energy intake in relation to bariatric surgery for obesity
Ochner, C. N., Gibson, C. D., Carnell, S., Dambkowski, C. L., & Geliebter, A. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.04.032 · Cited by 50
“This effect on reward processing in the mesolimbic dopaminergic pathway may be an integral part of ghrelin's orexigenic action [17,18], supported by evidence that blocking ghrelin receptors in the VTA decreases food intake [16].”
Wei, X., Sun, B., Chen, K., Lv, B., Luo, X. M., & Yan, J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.05.001 · Cited by 45
López‐Ferreras, L., Richard, J. E., Anderberg, R. H., Nilsson, F. H., Olandersson, K., Kanoski, S. E., & Skibicka, K. P. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.02.011 · Cited by 45
Jerabek, P., Havlickova, T., Puskina, N., Charalambous, C., Lapka, M., Kačer, P., & Šustková-Fišerová, M. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.09.013 · Cited by 45
“Sustkova-Fiserova). receptors (GHSR1A1) are expressed in important reward related areas including striatum, nucleus accumbens (NAC2), amygdala, prefrontal cortex, hippocampus, and ventral tegmental area (VTA3) (Abizaid et al., 2006; Ferrini et al., 2009; Howard et al., 1996; Landgren et al., 2011; Naleid et al., 2005;…”
BackgroundLin, X., Wang, L., Zhao, J., He, L., Cui, L., Gao, Y., Chen, C., Fan, Y., Bai, L., & Li, Y. (2020) · Nano Today · doi:10.1016/j.nantod.2020.101010 · Cited by 45
Leptin reduces food intake via a dopamine D2 receptor-dependent mechanism
Billes, S. K., Simonds, S. E., & Cowley, M. A. (2012) · Molecular Metabolism · doi:10.1016/j.molmet.2012.07.003 · Cited by 47
“Furthermore, leptin and ghrelin signaling in the VTA can influence short-term feeding in mice, and midbrain leptin signaling is important for locomotor sensitization to amphetamine [6,7,19].”
Chakravarthy, V. S., Balasubramani, P. P., Mandali, A., Jahanshahi, M., & Moustafa, A. A. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2018.06.032 · Cited by 45
Circadian regulation of appetite and time restricted feeding
Page, A. J., Christie, S., Symonds, E. L., & Li, H. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.112873 · Cited by 44
Metabolic insights from a GHSR-A203E mutant mouse model
Torz, L., Osborne-Lawrence, S. L., Rodriguez, J. A., He, Z., Cornejo, M. P., Mustafá, E. R., Jin, C., Petersen, N., Hedegaard, M. A., Nybo, M. L., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101004 · Cited by 44
Cornejo, M. P., Mustafá, E. R., Barrile, F., Cassano, D., Francesco, P. N. D., Raingo, J., & Perelló, M. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.10.017 · Cited by 46
Morley, K. C., Perry, C. J., Watt, J., Hurzeler, T. P., Leggio, L., Lawrence, A. J., & Haber, P. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.1892641 · Cited by 44
“possible role of the ghrelin system in the mechanisms that regulate the onset and maintenance of AUD [115].”
BackgroundMaric, T., Sedki, F., Ronfard, B., Chafetz, D., & Shalev, U. (2011) · Addiction Biology · doi:10.1111/j.1369-1600.2011.00396.x · Cited by 44
“For example, GHS-R are expressed in dopamine (DA) neurons in the ventral tegmental area (VTA; Abizaid et al. 2006; Zigman et al. 2006), an important structure in the mesolimbic DA system that is critically involved in the rewarding and reinforcing effect of natural rewards and drugs of abuse (Wise…”
BackgroundZheng, D., de Vaca, S. C., & Carr, K. D. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.10.021 · Cited by 44
“All of these peripheral signals interact with the brain dopamine system (e.g., Deroche et al., 1995; Abizaid et al., 2006; Bondy et al., 1992; Figlewicz et al., 2003).”
BackgroundFeeding Induced by Cannabinoids Is Mediated Independently of the Melanocortin System
Sinnayah, P., Jobst, E. E., Rathner, J. A., Caldera-Siu, A. D., Tonelli-Lemos, L., Eusterbrock, A. J., Enriori, P. J., Pothos, E. N., Grove, K. L., & Cowley, M. A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002202 · Cited by 45
“Consistent with the hypothesis that dopaminergic activity in the VTA regulates feeding, it has recently been reported that ghrelin increases the firing rate of dopaminergic VTA neurons and that ghrelin injected into the VTA increases feeding in rats [14].”
BackgroundGhrelin enhances cue-induced bar pressing for high fat food
St-Onge, V., Watts, A. J., & Abizaid, A. B. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.11.005 · Cited by 46
Self-citationHedonics Act in Unison with the Homeostatic System to Unconsciously Control Body Weight
Münzberg, H., Qualls‐Creekmore, E., Yu, S., Morrison, C. D., & Berthoud, H. (2016) · Frontiers in Nutrition · doi:10.3389/fnut.2016.00006 · Cited by 43
Naef, L., Seabrook, L. T., Hsiao, J., Li, C., & Borgland, S. L. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14291 · Cited by 42
“Insulin (Figlewicz et al., 2003; Liu et al., 2013), leptin (Figlewicz et al., 2003; Leshan et al., 2010), glucagon-like peptide-1(GLP-1) (G€oke et al., 1995; Merchenthaler et al., 1999) and ghrelin receptors (Abizaid et al., 2006) are located on tyrosine hydroxylase (TH)-positive neurons in the VTA.”
BackgroundFritz, E. M., Singewald, N., & Bundel, D. D. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.594484 · Cited by 45
Faulconbridge, L. F., Grill, H. J., Kaplan, J. M., & Daniels, D. (2008) · Brain Research · doi:10.1016/j.brainres.2008.04.068 · Cited by 43
“Several studies directly implicate catecholaminergic pathways arising from the NTS in the hyperphagic response to peripheral or forebrain administration of ghrelin (Abizaid et al., 2006; Brunetti et al., 2002; Date et al., 2006; Jerlhag et al., 2006).”
BackgroundFeng, D. D., Yang, S.-K., Loudes, C., Simon, A., Al-Sarraf, T., Culler, M., Alvear-Perez, R., Llorens-Cortes, C., Chen, C., Epelbaum, J., et al. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07787.x · Cited by 41
“The demonstration that the ghrelin-induced increase in GHRH neuron excitability is, at least in part, a consequence of a ghrelin-induced decrease in GABAergic transmission efficacy onto GHRH neurons, without affecting glutamate inputs, matches previous similar observations on inhibitory postsynaptic spontaneous curren…”
BackgroundResultChen, L., Lu, Y., Chen, H., Huang, S., Guo, Y.-R., Zhang, J.-Y., Li, Q.-X., Luo, C., Lin, S., Chen, Z.-N., et al. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108114 · Cited by 41
Overlapping representations of food and social stimuli in mouse VTA dopamine neurons
Willmore, L., Minerva, A. R., Engelhard, B., Murugan, M., McMannon, B., Oak, N., Thiberge, S. Y., Peña, C. J., & Witten, I. B. (2023) · Neuron · doi:10.1016/j.neuron.2023.08.003 · Cited by 45
GHS-R1A antagonism reduces alcohol but not sucrose preference in prairie voles
Stevenson, J. R., Buirkle, J. M., Buckley, L., Young, K., Albertini, K. M., & Bohidar, A. E. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.04.001 · Cited by 43
Lamont, E. W., Bruton, J., Blum, I. D., & Abizaid, A. B. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12390 · Cited by 42
“These mice were generated using a mixed C57BL/6J and DBA strain as background and the coding region of the ghsr locus was precisely deleted and replaced with an in-frame lacZ reporter gene (Abizaid et al., 2006; Diano et al., 2006).”
BackgroundMethodSelf-citationBonaventura, E. M. D., Botticelli, L., Bello, F. D., Giorgioni, G., Piergentili, A., Quaglia, W., Cifani, C., & Bonaventura, M. V. M. D. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105847 · Cited by 46
Koopmann, A., Schuster, R., & Kiefer, F. (2016) · Biological Psychology · doi:10.1016/j.biopsycho.2016.12.012 · Cited by 41
Monteleone, P., Tortorella, A. A. V., Scognamiglio, P., Serino, I., Monteleone, A. M., & Maj, M. (2012) · Neuropsychobiology · doi:10.1159/000341877 · Cited by 41
Nesfatin-1 acts on the dopaminergic reward pathway to inhibit food intake
Chen, X., Shu, X. Y., Cong, Z., Jiang, Z., & Jiang, H. F. (2015) · Neuropeptides · doi:10.1016/j.npep.2015.07.004 · Cited by 41
“The anorexigenic peptide leptin inhibits the firing of dopamine neurons (Hommel et al., 2006), while the orexigenic peptide ghrelin increases neuronal dopamine activity in the VTA (Abizaid et al., 2006).”
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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