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The role of ghrelin in addiction: a review

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Abstract

Rationale

Ghrelin is a fast-acting hormone that is produced primarily by the stomach and by the brain although in smaller quantities. The regulation and the secretion of ghrelin are complex and not limited to aspects of feeding. Ghrelin exerts powerful effects on multiple processes, and it has been demonstrated that it mediates the rewarding properties of food as well as of drugs of abuse.

Objectives

The purpose of this review is to summarize the findings of preclinical and clinical studies related to ghrelin’s possible role in addiction for each specific class of substances. Questions related to ghrelin’s involvement in addiction are highlighted. Recurrent methodological issues that render the interpretation of the findings challenging are discussed. Also, the potential of targeting ghrelin as a pharmacologic treatment strategy for addiction is explored.

Results

Ghrelin signaling is implicated in the mediation of behavioral and biochemical effects of drugs of abuse that are cardinal for the development of addiction, especially for alcohol, nicotine, and stimulants. The available literature implicating ghrelin in opioid or cannabis use disorders is currently limited and inconclusive.

Conclusions

There is intriguing, although not always consistent, evidence for the involvement of ghrelin signaling in aspects of addiction, especially in the cases of alcohol, nicotine, and stimulants. Further research, particularly in humans, is recommended to replicate and expand on the findings of the current literature. Improved and novel methodologies that take into account the volatile and complex nature of ghrelin are required to clarify the inconsistencies of the findings.

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References

  • Abizaid A (2009) Ghrelin and dopamine: new insights on the peripheral regulation of appetite. J Neuroendocrinol 21:787–793. doi:10.1111/j.1365-2826.2009.01896.x

    CAS  PubMed  Google Scholar 

  • Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschop MH, Gao XB, Horvath TL (2006) Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 116:3229–3239. doi:10.1172/JCI29867

    CAS  PubMed Central  PubMed  Google Scholar 

  • Abizaid A, Mineur YS, Roth RH, Elsworth JD, Sleeman MW, Picciotto MR, Horvath TL (2011) Reduced locomotor responses to cocaine in ghrelin-deficient mice. Neuroscience 192:500–506. doi:10.1016/j.neuroscience.2011.06.001

    CAS  PubMed  Google Scholar 

  • Addolorato G, Capristo E, Leggio L, Ferrulli A, Abenavoli L, Malandrino N, Farnetti S, Domenicali M, D’Angelo C, Vonghia L, Mirijello A, Cardone S, Gasbarrini G (2006) Relationship between ghrelin levels, alcohol craving, and nutritional status in current alcoholic patients. Alcohol Clin Exp Res 30:1933–1937. doi:10.1111/j.1530-0277.2006.00238.x

    CAS  PubMed  Google Scholar 

  • Alen F, Crespo I, Ramirez-Lopez MT, Jagerovic N, Goya P, de Fonseca FR, de Heras RG, Orio L (2013) Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism. PLoS One 8:e60918. doi:10.1371/journal.pone.0060918

    CAS  PubMed Central  PubMed  Google Scholar 

  • Al-Massadi O, Gabellieri E, Trujillo ML, Senaris R, Pagotto U, Pasquali R, Casanueva FF, Seoane LM (2010) Peripheral endocannabinoid system-mediated actions of rimonabant on growth hormone secretion are ghrelin-dependent. J Neuroendocrinol 22:1127–1136. doi:10.1111/j.1365-2826.2010.02065.x

    CAS  PubMed  Google Scholar 

  • Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ (2004) AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279:12005–12008. doi:10.1074/jbc.C300557200

    CAS  PubMed  Google Scholar 

  • Arora S, Anubhuti (2006) Role of neuropeptides in appetite regulation and obesity—a review. Neuropeptides 40:375–401. doi:10.1016/j.npep.2006.07.001

    CAS  PubMed  Google Scholar 

  • Arvat E, Di Vito L, Broglio F, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E (2000) Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Investig 23:493–495

    CAS  Google Scholar 

  • Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M (2001) Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120:337–345. doi:10.1053/gast.2001.22158

    CAS  PubMed  Google Scholar 

  • Avena NM, Rada P, Hoebel BG (2008) Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev 32:20–39. doi:10.1016/j.neubiorev.2007.04.019

    CAS  PubMed Central  PubMed  Google Scholar 

  • Badaoui A, De Saeger C, Duchemin J, Gihousse D, de Timary P, Starkel P (2008) Alcohol dependence is associated with reduced plasma and fundic ghrelin levels. Eur J Clin Investig 38:397–403. doi:10.1111/j.1365-2362.2008.01947.x

    CAS  Google Scholar 

  • Bahi A, Tolle V, Fehrentz JA, Brunel L, Martinez J, Tomasetto CL, Karam SM (2013) Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference. Peptides 43:48–55. doi:10.1016/j.peptides.2013.02.008

    CAS  PubMed  Google Scholar 

  • Barkan AL, Dimaraki EV, Jessup SK, Symons KV, Ermolenko M, Jaffe CA (2003) Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J Clin Endocrinol Metab 88:2180–2184. doi:10.1210/jc.2002-021169

    CAS  PubMed  Google Scholar 

  • Bell SM, Stewart RB, Thompson SC, Meisch RA (1997) Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats. Psychopharmacology 131:1–8. doi:10.1007/s002130050258

    CAS  PubMed  Google Scholar 

  • Bennett PA, Thomas GB, Howard AD, Feighner SD, van der Ploeg LH, Smith RG, Robinson IC (1997) Hypothalamic growth hormone secretagogue-receptor (GHS-R) expression is regulated by growth hormone in the rat. Endocrinology 138:4552–4557. doi:10.1210/endo.138.11.5476

    CAS  PubMed  Google Scholar 

  • Black SC (2004) Cannabinoid receptor antagonists and obesity. Curr Opin Investig Drugs 5:389–394

    CAS  PubMed  Google Scholar 

  • Bouret SG, Draper SJ, Simerly RB (2004) Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 24:2797–2805. doi:10.1523/jneurosci.5369-03.2004

    CAS  PubMed  Google Scholar 

  • Bouros D, Tzouvelekis A, Anevlavis S, Doris M, Tryfon S, Froudarakis M, Zournatzi V, Kukuvitis A (2006) Smoking acutely increases plasma ghrelin concentrations. Clin Chem 52:777–778. doi:10.1373/clinchem.2005.065243

    CAS  PubMed  Google Scholar 

  • Calissendorff J, Danielsson O, Brismar K, Rojdmark S (2005) Inhibitory effect of alcohol on ghrelin secretion in normal man. Eur J Endocrinol 152:743–747. doi:10.1530/eje.1.01905

    CAS  PubMed  Google Scholar 

  • Calissendorff J, Danielsson O, Brismar K, Rojdmark S (2006) Alcohol ingestion does not affect serum levels of peptide YY but decreases both total and octanoylated ghrelin levels in healthy subjects. Metabolism 55:1625–1629

    CAS  PubMed  Google Scholar 

  • Cani PD, Montoya ML, Neyrinck AM, Delzenne NM, Lambert DM (2004) Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide. Br J Nutr 92:757–761

    CAS  PubMed  Google Scholar 

  • Carroll ME (1998) Acquisition and reacquisition (relapse) of drug abuse: modulation by alternative reinforcers. NIDA Res Monogr 169:6–25

    CAS  PubMed  Google Scholar 

  • Carroll ME, Lac ST (1998) Dietary additives and the acquisition of cocaine self-administration in rats. Psychopharmacology 137:81–89

    CAS  PubMed  Google Scholar 

  • Clifford S, Zeckler RA, Buckman S, Thompson J, Hart N, Wellman PJ, Smith RG (2011) Impact of food restriction and cocaine on locomotion in ghrelin- and ghrelin-receptor knockout mice. Addict Biol 16:386–392. doi:10.1111/j.1369-1600.2010.00253.x

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clifford PS, Rodriguez J, Schul D, Hughes S, Kniffin T, Hart N, Eitan S, Brunel L, Fehrentz JA, Martinez J, Wellman PJ (2012) Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors. Addict Biol 17:956–963. doi:10.1111/j.1369-1600.2011.00339.x

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cloninger CR (1994) Temperament and personality. Curr Opin Neurobiol 4:266–273

    CAS  PubMed  Google Scholar 

  • Cota D, Marsicano G, Lutz B, Vicennati V, Stalla GK, Pasquali R, Pagotto U (2003) Endogenous cannabinoid system as a modulator of food intake. Int J Obes 27:289–301. doi:10.1038/sj.ijo.802250

    CAS  Google Scholar 

  • Cowley M, Smith R, Diano S, Tschop M, Pronchuk N, Grove K, Stasburger C, Bidlingmaier M, Esterman M, Heiman M, Garcia-Segura L, Nillni E, Mendez P, Low M, Sotonyi P, Friedman J, Liu H, Pinto S, Colmers W, Cone R, Horvath T (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–661

    CAS  PubMed  Google Scholar 

  • Crowley WR, Ramoz G, Keefe KA, Torto R, Kalra SP, Hanson GR (2005) Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum-fed and schedule-fed rats. Neuroscience 132:167–173. doi:10.1016/j.neuroscience.2004.11.037

    CAS  PubMed  Google Scholar 

  • Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714–1719. doi:10.2337/diabetes.50.8.1714

    CAS  PubMed  Google Scholar 

  • Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A, Weigle DS (2002) Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med 8:643–644. doi:10.1038/nm0702-643

    CAS  PubMed  Google Scholar 

  • Cummings DE, Naleid AM, Figlewicz Lattemann DP (2007) Ghrelin: a link between energy homeostasis and drug abuse? Addict Biol 12:1–5. doi:10.1111/j.1369-1600.2007.00053.x

    PubMed  Google Scholar 

  • Davis KW, Wellman PJ, Clifford PS (2007) Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin. Regul Pept 140:148–152. doi:10.1016/j.regpep.2006.12.003

    CAS  PubMed Central  PubMed  Google Scholar 

  • DiLeone RJ, Georgescu D, Nestler EJ (2003) Lateral hypothalamic neuropeptides in reward and drug addiction. Life Sci 73:759–768

    CAS  PubMed  Google Scholar 

  • Doyle TG, Berridge KC, Gosnell BA (1993) Morphine enhances hedonic taste palatability in rats. Pharmacol Biochem Behav 46:745–749

    CAS  PubMed  Google Scholar 

  • Drewnowski A, Krahn DD, Demitrack MA, Nairn K, Gosnell BA (1992) Taste responses and preferences for sweet high-fat foods: evidence for opioid involvement. Physiol Behav 51:371–379

    CAS  PubMed  Google Scholar 

  • Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, Ghatei MA, Small C, Bloom SR (2005) Ghrelin increases food intake in obese as well as lean subjects. Int J Obes 29:1130–1136. doi:10.1038/sj/ijo.0803001

    CAS  Google Scholar 

  • Elmquist JK (2001) Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Int J Obes Relat Metab Disord 25(Suppl 5):S78–S82. doi:10.1038/sj.ijo.0801918

    CAS  PubMed  Google Scholar 

  • Fagerberg B, Hulten LM, Hulthe J (2003) Plasma ghrelin, body fat, insulin resistance, and smoking in clinically healthy men: the atherosclerosis and insulin resistance study. Metabolism 52:1460–1463

    CAS  PubMed  Google Scholar 

  • Fantino M, Hosotte J, Apfelbaum M (1986) An opioid antagonist, naltrexone, reduces preference for sucrose in humans. Am J Physiol 251:R91–R96

    CAS  PubMed  Google Scholar 

  • Grigson PS (2002) Like drugs for chocolate: separate rewards modulated by common mechanisms? Physiol Behav 76:389–395

    CAS  PubMed  Google Scholar 

  • Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Van der Ploeg LH, Howard AD (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48:23–29

    CAS  PubMed  Google Scholar 

  • Holden C (2001) ‘Behavioral’ addictions: do they exist? Science 294:980–982. doi:10.1126/science.294.5544.980

    CAS  PubMed  Google Scholar 

  • Hosoda H, Kojima M, Matsuo H, Kangawa K (2000) Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 279:909–913. doi:10.1006/bbrc.2000.4039

    CAS  PubMed  Google Scholar 

  • Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977

    CAS  PubMed  Google Scholar 

  • Jerlhag E (2008) Systemic administration of ghrelin induces conditioned place preference and stimulates accumbal dopamine. Addict Biol 13:358–363. doi:10.1111/j.1369-1600.2008.00125.x

    CAS  PubMed  Google Scholar 

  • Jerlhag E, Engel JA (2011) Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice. Drug Alcohol Depend 117:126–131. doi:10.1016/j.drugalcdep.2011.01.010

    CAS  PubMed  Google Scholar 

  • Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA (2006) Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addict Biol 11:45–54. doi:10.1111/j.1369-1600.2006.00002.x

    CAS  PubMed  Google Scholar 

  • Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA (2007) Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addict Biol 12:6–16. doi:10.1111/j.1369-1600.2006.00041.x

    CAS  PubMed  Google Scholar 

  • Jerlhag E, Egecioglu E, Landgren S, Salome N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA (2009) Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci U S A 106:11318–11323. doi:10.1073/pnas.0812809106

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jerlhag E, Egecioglu E, Dickson SL, Engel JA (2010) Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacology 211:415–422. doi:10.1007/s00213-010-1907-7

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jerlhag E, Landgren S, Egecioglu E, Dickson SL, Engel JA (2011) The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice. Alcohol 45:341–347. doi:10.1016/j.alcohol.2010.10.002

    CAS  PubMed  Google Scholar 

  • Jerlhag E, Janson AC, Waters S, Engel JA (2012) Concomitant release of ventral tegmental acetylcholine and accumbal dopamine by ghrelin in rats. PLoS One 7:e49557. doi:10.1371/journal.pone.0049557

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jerlhag E, Ivanoff L, Vater A, Engel JA (2014) Peripherally circulating ghrelin does not mediate alcohol-induced reward and alcohol intake in rodents. Alcohol Clin Exp Res 38:959–968. doi:10.1111/acer.12337

    CAS  PubMed  Google Scholar 

  • Kaur S, Ryabinin AE (2010) Ghrelin receptor antagonism decreases alcohol consumption and activation of perioculomotor urocortin-containing neurons. Alcohol Clin Exp Res 34:1525–1534. doi:10.1111/j.1530-0277.2010.01237.x

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim DJ, Yoon SJ, Choi B, Kim TS, Woo YS, Kim W, Myrick H, Peterson BS, Choi YB, Kim YK, Jeong J (2005) Increased fasting plasma ghrelin levels during alcohol abstinence. Alcohol Alcohol 40:76–79. doi:10.1093/alcalc/agh108

    CAS  PubMed  Google Scholar 

  • Kirkham TC (2005) Endocannabinoids in the regulation of appetite and body weight. Behav Pharmacol 16:297–313

    CAS  PubMed  Google Scholar 

  • Kirkham TC, Williams CM (2001) Endogenous cannabinoids and appetite. Nutr Res Rev 14:65–86. doi:10.1079/NRR200118

    CAS  PubMed  Google Scholar 

  • Kobeissy FH, Jeung JA, Warren MW, Geier JE, Gold MS (2008) Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in rats. Addict Biol 13:15–25. doi:10.1111/j.1369-1600.2007.00083.x

    CAS  PubMed  Google Scholar 

  • Kojima M, Kangawa K (2006) Drug insight: the functions of ghrelin and its potential as a multitherapeutic hormone. Nat Clin Pract Endocrinol Metab 2:80–88. doi:10.1038/ncpendmet0080

    CAS  PubMed  Google Scholar 

  • Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660

    CAS  PubMed  Google Scholar 

  • Kojima M, Hosoda H, Matsuo H, Kangawa K (2001) Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 12:118–122

    CAS  PubMed  Google Scholar 

  • Kokkinos A, Tentolouris N, Kyriakaki E, Argyrakopoulou G, Doupis J, Psallas M, Kyriaki D, Katsilambros N (2007) Differentiation in the short- and long-term effects of smoking on plasma total ghrelin concentrations between male nonsmokers and habitual smokers. Metabolism 56:523–527. doi:10.1016/j.metabol.2006.11.012

    CAS  PubMed  Google Scholar 

  • Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280:25196–25201. doi:10.1074/jbc.C500175200

    CAS  PubMed  Google Scholar 

  • Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, Harvey-White J, Liposits Z, Kunos G, Grossman AB, Fekete C, Korbonits M (2008) The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One 3 doi:10.1371/Journal.Pone.0001797

  • Koopmann A, von der Goltz C, Grosshans M, Dinter C, Vitale M, Wiedemann K, Kiefer F (2012) The association of the appetitive peptide acetylated ghrelin with alcohol craving in early abstinent alcohol dependent individuals. Psychoneuroendocrinology 37:980–986. doi:10.1016/j.psyneuen.2011.11.005

    CAS  PubMed  Google Scholar 

  • Korbonits M, Bustin SA, Kojima M, Jordan S, Adams EF, Lowe DG, Kangawa K, Grossman AB (2001) The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. J Clin Endocrinol Metab 86:881–887

    CAS  PubMed  Google Scholar 

  • Kraus T, Schanze A, Groschl M, Bayerlein K, Hillemacher T, Reulbach U, Kornhuber J, Bleich S (2005) Ghrelin levels are increased in alcoholism. Alcohol Clin Exp Res 29:2154–2157

    CAS  PubMed  Google Scholar 

  • Landgren S, Jerlhag E, Zetterberg H, Gonzalez-Quintela A, Campos J, Olofsson U, Nilsson S, Blennow K, Engel JA (2008) Association of pro-ghrelin and GHS-R1A gene polymorphisms and haplotypes with heavy alcohol use and body mass. Alcohol Clin Exp Res 32:2054–2061. doi:10.1111/j.1530-0277.2008.00793.x

    CAS  PubMed  Google Scholar 

  • Landgren S, Jerlhag E, Hallman J, Oreland L, Lissner L, Strandhagen E, Thelle DS, Zetterberg H, Blennow K, Engel JA (2010) Genetic variation of the ghrelin signaling system in females with severe alcohol dependence. Alcohol Clin Exp Res 34:1519–1524. doi:10.1111/j.1530-0277.2010.01236.x

    CAS  PubMed  Google Scholar 

  • Landgren S, Berglund K, Jerlhag E, Fahlke C, Balldin J, Berggren U, Zetterberg H, Blennow K, Engel JA (2011a) Reward-related genes and personality traits in alcohol-dependent individuals: a pilot case control study. Neuropsychobiology 64:38–46. doi:10.1159/000324992

    PubMed  Google Scholar 

  • Landgren S, Engel JA, Hyytia P, Zetterberg H, Blennow K, Jerlhag E (2011b) Expression of the gene encoding the ghrelin receptor in rats selected for differential alcohol preference. Behav Brain Res 221:182–188. doi:10.1016/j.bbr.2011.03.003

    CAS  PubMed  Google Scholar 

  • Landgren S, Simms JA, Hyytia P, Engel JA, Bartlett SE, Jerlhag E (2011c) Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats. Addict Biol 17:86–94. doi:10.1111/j.1369-1600.2010.00280.x

    PubMed  Google Scholar 

  • Langenberg C, Bergstrom J, Laughlin GA, Barrett-Connor E (2005) Ghrelin and the metabolic syndrome in older adults. J Clin Endocrinol Metab 90:6448–6453. doi:10.1210/jc.2005-1358

    CAS  PubMed  Google Scholar 

  • Lee H, Joe KH, Kim W, Park J, Lee DH, Sung KW, Kim DJ (2006) Increased leptin and decreased ghrelin level after smoking cessation. Neurosci Lett 409:47–51. doi:10.1016/j.neulet.2006.09.013

    CAS  PubMed  Google Scholar 

  • Leggio L (2013) Studying the role of feeding-related pathways in alcoholism via human laboratory studies. Alcohol Alcohol 48:27–27

    Google Scholar 

  • Leggio L, Ferrulli A, Cardone S, Nesci A, Miceli A, Malandrino N, Capristo E, Canestrelli B, Monteleone P, Kenna GA, Swift RM, Addolorato G (2012) Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving. Addict Biol 17:452–464. doi:10.1111/j.1369-1600.2010.00308.x

    CAS  PubMed  Google Scholar 

  • Leggio L, Schwandt ML, Oot EN, Dias AA, Ramchandani VA (2013) Fasting-induced increase in plasma ghrelin is blunted by intravenous alcohol administration: a within-subject placebo-controlled study. Psychoneuroendocrinology. doi:10.1016/j.psyneuen.2013.09.005

    PubMed  Google Scholar 

  • Lim CT, Kola B, Feltrin D, Perez-Tilve D, Tschop MH, Grossman AB, Korbonits M (2013) Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism. Mol Cell Endocrinol 365:303–308. doi:10.1016/j.mce.2012.11.007

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lyons AM, Lowery EG, Sparta DR, Thiele TE (2008) Effects of food availability and administration of orexigenic and anorectic agents on elevated ethanol drinking associated with drinking in the dark procedures. Alcohol Clin Exp Res 32:1962–1968. doi:10.1111/j.1530-0277.2008.00784.x

    CAS  PubMed Central  PubMed  Google Scholar 

  • Maldonado-Irizarry CS, Swanson CJ, Kelley AE (1995) Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus. J Neurosci 15:6779–6788

    CAS  PubMed  Google Scholar 

  • Malik S, McGlone F, Bedrossian D, Dagher A (2008) Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab 7:400–409. doi:10.1016/j.cmet.2008.03.007

    CAS  PubMed  Google Scholar 

  • Maric T, Sedki F, Ronfard B, Chafetz D, Shalev U (2012) A limited role for ghrelin in heroin self-administration and food deprivation-induced reinstatement of heroin seeking in rats. Addict Biol 17:613–622. doi:10.1111/j.1369-1600.2011.00396.x

    CAS  PubMed  Google Scholar 

  • Mear Y, Enjalbert A, Thirion S (2013) GHS-R1a constitutive activity and its physiological relevance. Front Neurosci 7:87. doi:10.3389/fnins.2013.00087

    PubMed Central  PubMed  Google Scholar 

  • Mohs ME, Watson RR, Leonard-Green T (1990) Nutritional effects of marijuana, heroin, cocaine, and nicotine. J Am Diet Assoc 90:1261–1267

    CAS  PubMed  Google Scholar 

  • Mucha RF, Iversen SD (1986) Increased food intake after opioid microinjections into nucleus accumbens and ventral tegmental area of rat. Brain Res 397:214–224. doi:10.1016/0006-8993(86)90622-0

    CAS  PubMed  Google Scholar 

  • Mutschler J, Graf N, Spanaus KS, Rossler W, Hergan K, Binkert CA, Gutzeit A (2012) Circulating ghrelin levels are not associated with craving and withdrawal symptoms in acute nicotine withdrawal. Psychiatr Danub 24:229–230

    PubMed  Google Scholar 

  • Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H, Yutani C, Kangawa K (2001) Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 104:2034–2038. doi:10.1161/hc4201.097836

    CAS  PubMed  Google Scholar 

  • Naleid AM, Grace MK, Cummings DE, Levine AS (2005) Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides 26:2274–2279. doi:10.1016/j.peptides.2005.04.025

    CAS  PubMed  Google Scholar 

  • Nedvidkova J, Krykorkova I, Bartak V, Papezova H, Gold PW, Alesci S, Pacak K (2003) Loss of meal-induced decrease in plasma ghrelin levels in patients with anorexia nervosa. J Clin Endocrinol Metab 88:1678–1682

    CAS  PubMed  Google Scholar 

  • Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445–1449. doi:10.1038/nn1578

    CAS  PubMed  Google Scholar 

  • Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschop M (2001) Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 145:669–673

    CAS  PubMed  Google Scholar 

  • Pontieri FE, Tanda G, DiChiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci U S A 92:12304–12308. doi:10.1073/pnas.92.26.12304

    CAS  PubMed Central  PubMed  Google Scholar 

  • Poykko SM, Kellokoski E, Ukkola O, Kauma H, Paivansalo M, Kesaniemi YA, Horkko S (2006) Plasma ghrelin concentrations are positively associated with carotid artery atherosclerosis in males. J Intern Med 260:43–52. doi:10.1111/j.1365-2796.2006.01661.x

    CAS  PubMed  Google Scholar 

  • Quarta D, DiFrancesco C, Meletto S, Mangiarini L, Heidbreder C, Hedou G (2009) Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens. Neurochem Int 54:89–94

    CAS  PubMed  Google Scholar 

  • Rada PV, Mark GP, Yeomans JJ, Hoebel BG (2000) Acetylcholine release in ventral tegmental area by hypothalamic self-stimulation, eating, and drinking. Pharmacol Biochem Behav 65:375–379

    CAS  PubMed  Google Scholar 

  • Richardson KA, Aston-Jones G (2012) Lateral hypothalamic orexin/hypocretin neurons that project to ventral tegmental area are differentially activated with morphine preference. J Neurosci 32:3809–3817. doi:10.1523/jneurosci.3917-11.2012

    CAS  PubMed Central  PubMed  Google Scholar 

  • Saad MF, Bernaba B, Hwu CM, Jinagouda S, Fahmi S, Kogosov E, Boyadjian R (2002) Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab 87:3997–4000

    CAS  PubMed  Google Scholar 

  • Sakata I, Nakamura K, Yamazaki M, Matsubara M, Hayashi Y, Kangawa K, Sakai T (2002) Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides 23:531–536. doi:10.1016/S0196-9781(01)00633-7

    CAS  PubMed  Google Scholar 

  • Schellekens H, Dinan TG, Cryan JF (2010) Lean mean fat reducing “ghrelin” machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology 58:2–16. doi:10.1016/j.neuropharm.2009.06.024

    CAS  PubMed  Google Scholar 

  • Schellekens H, Dinan TG, Cryan JF (2013a) Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward. Front Neurosci 7:148. doi:10.3389/fnins.2013.00148

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schellekens H, van Oeffelen WE, Dinan TG, Cryan JF (2013b) Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling. J Biol Chem 288:181–191. doi:10.1074/jbc.M112.382473

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sibilia V, Lattuada N, Rapetti D, Pagani F, Vincenza D, Bulgarelli I, Locatelli V, Guidobono F, Netti C (2006) Ghrelin inhibits inflammatory pain in rats: involvement of the opioid system. Neuropharmacology 51:497–505. doi:10.1016/j.neuropharm.2006.04.009

    CAS  PubMed  Google Scholar 

  • Skibicka KP, Dickson SL (2011) Ghrelin and food reward: the story of potential underlying substrates. Peptides 32:2265–2273. doi:10.1016/j.peptides.2011.05.016

    CAS  PubMed  Google Scholar 

  • Stratford TR, Wirtshafter D (2012) Evidence that the nucleus accumbens shell, ventral pallidum, and lateral hypothalamus are components of a lateralized feeding circuit. Behav Brain Res 226:548–554. doi:10.1016/j.bbr.2011.10.014

    CAS  PubMed Central  PubMed  Google Scholar 

  • Suchankova P, Jerlhag E, Jayaram-Lindstrom N, Nilsson S, Toren K, Rosengren A, Engel JA, Franck J (2013a) Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence. PLoS One 8:e61242. doi:10.1371/journal.pone.0061242

    CAS  PubMed Central  PubMed  Google Scholar 

  • Suchankova P, Steensland P, Fredriksson I, Engel JA, Jerlhag E (2013b) Ghrelin receptor (GHS-R1A) antagonism suppresses both alcohol consumption and the alcohol deprivation effect in rats following long-term voluntary alcohol consumption. PLoS One 8:e71284. doi:10.1371/journal.pone.0071284

    CAS  PubMed Central  PubMed  Google Scholar 

  • Szulc M, Mikolajczak PL, Geppert B, Wachowiak R, Dyr W, Bobkiewicz-Kozlowska T (2013) Ethanol affects acylated and total ghrelin levels in peripheral blood of alcohol-dependent rats. Addict Biol 18:689–701. doi:10.1111/adb.12025

    CAS  PubMed  Google Scholar 

  • Tanda G, Di Chiara G (1998) A dopamine-mu1 opioid link in the rat ventral tegmentum shared by palatable food (Fonzies) and non-psychostimulant drugs of abuse. Eur J Neurosci 10:1179–1187

    CAS  PubMed  Google Scholar 

  • Tessari M, Catalano A, Pellitteri M, Di Francesco C, Marini F, Gerrard PA, Heidbreder CA, Melotto S (2007) Correlation between serum ghrelin levels and cocaine-seeking behaviour triggered by cocaine-associated conditioned stimuli in rats. Addict Biol 12:22–29. doi:10.1111/j.1369-1600.2007.00052.x

    CAS  PubMed  Google Scholar 

  • Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, Wells T (2004) Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 145:234–242. doi:10.1210/en.2003-0899

    CAS  PubMed  Google Scholar 

  • Tomoda K, Kubo K, Nishii Y, Yamamoto Y, Yoshikawa M, Kimura H (2012) Changes of ghrelin and leptin levels in plasma by cigarette smoke in rats. J Toxicol Sci 37:131–138

    CAS  PubMed  Google Scholar 

  • Toshinai K, Mondal MS, Nakazato M, Date Y, Murakami N, Kojima M, Kangawa K, Matsukura S (2001) Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem Biophys Res Commun 281:1220–1225. doi:10.1006/bbrc.2001.4518

    CAS  PubMed  Google Scholar 

  • Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Murakami N, Miyazato M, Kangawa K, Nakazato M (2006) Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology 147:2306–2314. doi:10.1210/en.2005-1357

    CAS  PubMed  Google Scholar 

  • Tschop M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407:908–913. doi:10.1038/35038090

    CAS  PubMed  Google Scholar 

  • Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R, Folwaczny C (2001) Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Investig 24:RC19–RC21

    CAS  Google Scholar 

  • Tucci SA, Rogers EK, Korbonits M, Kirkham TC (2004) The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol 143:520–523. doi:10.1038/sj.bjp.0705968

    CAS  PubMed Central  PubMed  Google Scholar 

  • Urstadt KR, Coop SH, Banuelos BD, Stanley BG (2013a) Behaviorally specific versus non-specific suppression of accumbens shell-mediated feeding by ipsilateral versus bilateral inhibition of the lateral hypothalamus. Behav Brain Res 257:230–241. doi:10.1016/j.bbr.2013.09.048

    CAS  PubMed  Google Scholar 

  • Urstadt KR, Kally P, Zaidi SF, Stanley BG (2013b) Ipsilateral feeding-specific circuits between the nucleus accumbens shell and the lateral hypothalamus: regulation by glutamate and GABA receptor subtypes. Neuropharmacology 67:176–182. doi:10.1016/j.neuropharm.2012.10.027

    CAS  PubMed  Google Scholar 

  • van der Lely AJ, Tschop M, Heiman ML, Ghigo E (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25:426–457. doi:10.1210/er.2002-0029

    PubMed  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ (2003a) The addicted human brain: insights from imaging studies. J Clin Invest 111:1444–1451. doi:10.1172/JCI18533

    CAS  PubMed Central  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Maynard L, Jayne M, Fowler JS, Zhu W, Logan J, Gatley SJ, Ding YS, Wong C, Pappas N (2003b) Brain dopamine is associated with eating behaviors in humans. Int J Eat Disord 33:136–142. doi:10.1002/eat.10118

    PubMed  Google Scholar 

  • Wellman PJ, Davis KW, Nation JR (2005) Augmentation of cocaine hyperactivity in rats by systemic ghrelin. Regul Pept 125:151–154. doi:10.1016/j.regpep.2004.08.013

    CAS  PubMed  Google Scholar 

  • Wellman PJ, Hollas CN, Elliott AE (2008) Systemic ghrelin sensitizes cocaine-induced hyperlocomotion in rats. Regul Pept 146:33–37. doi:10.1016/j.regpep.2007.07.007

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wellman PJ, Clifford PS, Rodriguez J, Hughes S, Eitan S, Brunel L, Fehrentz JA, Martinez J (2011) Pharmacologic antagonism of ghrelin receptors attenuates development of nicotine induced locomotor sensitization in rats. Regul Pept 172:77–80. doi:10.1016/j.regpep.2011.08.014

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wisse BE, Frayo RS, Schwartz MW, Cummings DE (2001) Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 142:3292–3301

    CAS  PubMed  Google Scholar 

  • Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992

    CAS  PubMed  Google Scholar 

  • Wurst FM, Graf I, Ehrenthal HD, Klein S, Backhaus J, Blank S, Graf M, Pridzun L, Wiesbeck GA, Junghanns K (2007) Gender differences for ghrelin levels in alcohol-dependent patients and differences between alcoholics and healthy controls. Alcohol Clin Exp Res 31:2006–2011. doi:10.1111/j.1530-0277.2007.00527.x

    CAS  PubMed  Google Scholar 

  • Yeomans MR, Gray RW (1997) Effects of naltrexone on food intake and changes in subjective appetite during eating: evidence for opioid involvement in the appetizer effect. Physiol Behav 62:15–21

    CAS  PubMed  Google Scholar 

  • Yoon SJ, Pae CU, Lee H, Choi B, Kim TS, Lyoo IK, Kwon DH, Kim DJ (2005) Ghrelin precursor gene polymorphism and methamphetamine dependence in the Korean population. Neurosci Res 53:391–395. doi:10.1016/j.neures.2005.08.013

    CAS  PubMed  Google Scholar 

  • Zigman JM, Elmquist JK (2003) Minireview: from anorexia to obesity—the yin and yang of body weight control. Endocrinology 144:3749–3756. doi:10.1210/en.2003-0241

    CAS  PubMed  Google Scholar 

  • Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494:528–548. doi:10.1002/cne.20823

    CAS  PubMed  Google Scholar 

  • Zimmermann U, Buchmann A, Steffin B, Dieterle C, Uhr M (2006) Alcohol administration acutely inhibits ghrelin secretion in an experiment involving psychosocial stress. Addict Biol 12:17–21

    Google Scholar 

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The authors have no conflict of interest to report.

Funding

Support for this manuscript was provided by the Mental Illness, Research, Education and Clinical Center (MIRECC) and by the National Center for PTSD, Clinical Neurosciences Division, VA CT Healthcare System, West Haven, CT, USA.

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  1. Department of Psychiatry, VA St. Louis Health Care System, 915 North Grand Blvd, St. Louis, MO, 63106, USA

    Vassilis N. Panagopoulos

  2. Department of Psychiatry, Washington University, 1 Brookings Dr., St. Louis, MO, 63130, USA

    Vassilis N. Panagopoulos

  3. Department of Psychiatry, VA Connecticut Healthcare System, Yale University School of Medicine, West Haven, CT, USA

    Elizabeth Ralevski

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Panagopoulos, V.N., Ralevski, E. The role of ghrelin in addiction: a review. Psychopharmacology 231, 2725–2740 (2014). https://doi.org/10.1007/s00213-014-3640-0

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