Ghrelin's role in the hypothalamic-pituitary-adrenal axis stress response: Implications for mood disorders

Biological Psychiatry

Volumn 78, Issue 1, 2015, Pages 19-27

  Spencer, Sarah J ^a   Emmerzaal, Tim L ^b   Kozicz, Tamas ^b,c   Andrews, Zane B ^d  

^a RMIT UNIVERSITY   (Australia)

^b RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^c TULANE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d MONASH UNIVERSITY   (Australia)

Author keywords

Centrally projecting Edinger Westphal nucleus; Depression; Ghrelin; Hypothalamic pituitary adrenal axis; Paraventricular nucleus of the hypothalamus; Pituitary; Stress

Indexed keywords

GHRELIN;

AMYGDALOID NUCLEUS; ANXIETY DISORDER; APPETITE; DEPRESSION; EDINGER WESTPHAL NUCLEUS; ENERGY BALANCE; FEAR; FEEDING BEHAVIOR; HIPPOCAMPUS; HORMONAL REGULATION; HUMAN; HYPOTHALAMUS HYPOPHYSIS ADRENAL SYSTEM; LOCUS CERULEUS; MOOD DISORDER; MOTIVATION; NEUROMODULATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; STRESS; VENTRAL TEGMENTUM; ANIMAL; FEEDBACK SYSTEM; HYPOPHYSIS ADRENAL SYSTEM; HYPOTHALAMUS HYPOPHYSIS SYSTEM; MENTAL STRESS; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; FEEDBACK, PHYSIOLOGICAL; GHRELIN; HUMANS; HYPOTHALAMO-HYPOPHYSEAL SYSTEM; MOOD DISORDERS; PITUITARY-ADRENAL SYSTEM; STRESS, PSYCHOLOGICAL;

EID: 84942984855     PISSN: 00063223     EISSN: 18732402     Source Type: Journal    
DOI: 10.1016/j.biopsych.2014.10.021     Document Type: Review

References (118)

1. 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.
2. Tschop M, Smiley DL, Heiman ML (2000): Ghrelin induces adiposity in rodents. Nature 407:908-913.
3. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001): A role for ghrelin in the central regulation of feeding. Nature 409:194-198.
4. Spencer SJ, Xu L, Clarke MA, Lemus M, Reichenbach A, Geenen B, et al. (2012): Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol Psychiatry 72:457-465.
5. Carlini VP, Monzon ME, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, De Barioglio SR (2002): Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 299:739-743.
6. Lutter M, Krishnan V, Russo SJ, Jung S, McClung CA, Nestler EJ (2008): Orexin signaling mediates the antidepressant-like effect of calorie restriction. J Neurosci 28:3071-3075.
7. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, et al. (2001): A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 74:143-147.
8. Kanehisa M, Akiyoshi J, Kitaichi T, Matsushita H, Tanaka E, Kodama K, et al. (2006): Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats. Prog Neuro-psychopharmacol Biol Psychiatry 30:1403-1407.
9. Nakashima K, Akiyoshi J, Hatano K, Hanada H, Tanaka Y, Tsuru J, et al. (2008): Ghrelin gene polymorphism is associated with depression, but not panic disorder. Psychiatr Genet 18:257.
10. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, et al. (2003): The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649-661.
11. Hou Z, Miao Y, Gao L, Pan H, Zhu S (2006): Ghrelin-containing neuron in cerebral cortex and hypothalamus linked with the DVC of brainstem in rat. Regul Pept 134:126-131.
12. Lu S, Guan JL, Wang QP, Uehara K, Yamada S, Goto N, et al. (2002): Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus. Neurosci Lett 321:157-160.
13. Sato T, Fukue Y, Teranishi H, Yoshida Y, Kojima M (2005): Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-d-glucose administration. Endocrinology 146:2510-2516.
14. Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, Shimbara T, et al. (2003): Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology 144:1506-1512.
15. Sakata I, Nakano Y, Osborne-Lawrence S, Rovinsky SA, Lee CE, Perello M, et al. (2009): Characterization of a novel ghrelin cell reporter mouse. Regul Pept 155:91-98.
16. Furness JB, Hunne B, Matsuda N, Yin L, Russo D, Kato I, et al. (2011): Investigation of the presence of ghrelin in the central nervous system of the rat and mouse. Neuroscience 193:1-9.
17. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008): Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132:387-396.
18. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, et al. (2008): Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA 105:6320-6325.
19. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, et al. (1997): Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48:23-29.
20. Perello M, Scott MM, Sakata I, Lee CE, Chuang JC, Osborne-Lawrence S, et al. (2012): Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain. J Comp Neurol 520:281-294.
21. Smith JT, Reichenbach A, Lemus M, Mani BK, Zigman JM, Andrews ZB (2013): An eGFP-expressing subpopulation of growth hormone secreta-gogue receptor cells are distinct from kisspeptin, tyrosine hydroxylase, and RFamide-related peptide neurons in mice. Peptides 47:45-53.
22. 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.
23. Mani BK, Walker AK, Lopez Soto EJ, Raingo J, Lee CE, Perello M, et al. (2014): Neuroanatomical characterization of a growth hormone secretagogue receptor-green fluorescent protein reporter mouse. J Comp Neurol 522:3644-3666.
24. Alvarez-Crespo M, Skibicka KP, Farkas I, Molnar CS, Egecioglu E, Hrabovszky E, et al. (2012): The amygdala as a neurobiological target for ghrelin in rats: Neuroanatomical, electrophysiological and behavioral evidence. PLoS One 7:e46321.
25. Cabral A, Suescun O, Zigman JM, Perello M (2012): Ghrelin indirectly activates hypophysiotropic CRF neurons in rodents. PLoS One 7:e31462.
26. Banks WA, Tschop M, Robinson SM, Heiman ML (2002): Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 302:822-827.
27. Cabral A, Fernandez G, Perello M (2013): Analysis of brain nuclei accessible to ghrelin present in the cerebrospinal fluid. Neuroscience 253:406-415.
28. Cabral A, Valdivia S, Fernandez G, Reynaldo M, Perello M (2014): Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: Critical role of brain accessibility. J Neuroendocrinol 26:542-554.
29. Schaeffer M, Langlet F, Lafont C, Molino F, Hodson DJ, Roux T, et al. (2013): Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc Natl Acad Sci USA 110:1512-1517.
30. Banks WA, Burney BO, Robinson SM (2008): Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood-brain barrier. Peptides 29:2061-2065.
31. Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, et al. (2008): The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 11:752-753.
32. Patterson ZR, Khazall R, Mackay H, Anisman H, Abizaid A (2013): Central ghrelin signaling mediates the metabolic response of C57BL/6 male mice to chronic social defeat stress. Endocrinology 154:1080-1091.
33. Raspopow K, Abizaid A, Matheson K, Anisman H (2010): Psycho-social stressor effects on cortisol and ghrelin in emotional and non-emotional eaters: Influence of anger and shame. Horm Behav 58:677-684.
34. Spencer SJ, Tilbrook A (2011): The glucocorticoid contribution to obesity. Stress 14:233-246.
35. Sapolsky RM, Romero LM, Munck AU (2000): How do gluco-corticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21:55-89.
36. Papadimitriou A, Priftis KN (2009): Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation 16:265-271.
37. Staufenbiel SM, Penninx BW, Spijker AT, Elzinga BM, Van Rossum EF (2013): Hair cortisol, stress exposure, and mental health in humans: A systematic review. Psychoneuroendocrinology 38:1220-1235.
38. Lloyd RB, Nemeroff CB (2011): The role of corticotropin-releasing hormone in the pathophysiology of depression: Therapeutic implications. Curr Top Med Chem 11:609-617.
39. Kristenssson E, Sundqvist M, Astin M, Kjerling M, Mattsson H, Dornonville De La Cour C, et al. (2006): Acute psychological stress raises plasma ghrelin in the rat. Regul Pept 134:114-117.
40. Ochi M, Tominaga K, Tanaka F, Tanigawa T, Shiba M, Watanabe T, et al. (2008): Effect of chronic stress on gastric emptying and plasma ghrelin levels in rats. Life Sci 82:862-868.
41. Zheng J, Dobner A, Babygirija R, Ludwig K, Takahashi T (2009): Effects of repeated restraint stress on gastric motility in rats. Am J Physiol Regul Integr Comp Physiol 296:R1358-R1365.
42. Patterson ZR, Ducharme R, Anisman H, Abizaid A (2010): Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor-deficient mice. Eur J Neurosci 32:632-639.
43. Rouach V, Bloch M, Rosenberg N, Gilad S, Limor R, Stern N, Greenman Y (2007): The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat. Psychoneuroendocrinology 32:693-702.
44. Zhao TJ, Sakata I, Li RL, Liang G, Richardson JA, Brown MS, et al. (2010): Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. Proc Natl Acad Sci USA 107:15868-15873.
45. Reichenbach A, Steyn FJ, Sleeman MW, Andrews ZB (2012): Ghrelin receptor expression and colocalisation with anterior pituitary hormones using a GHSR-GFP mouse line. Endocrinology 153:5452-5466.
46. Kadar A, Sanchez E, Wittmann G, Singru PS, Fuzesi T, Marsili A, et al. (2010): Distribution of hypophysiotropic thyrotropin-releasing hormone (TRH)-synthesizing neurons in the hypothalamic paraven-tricular nucleus of the mouse. J Comp Neurol 518:3948-3961.
47. Arvat E, Maccario M, Di Vito L, Broglio F, Benso A, Gottero C, et al. (2001): Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: Comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab 86:1169-1174.
48. Schmid DA, Held K, Ising M, Uhr M, Weikel JC, Steiger A (2005): Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls. Neuropsycho-pharmacology 30:1187-1192.
49. Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, De Barioglio SR (2004): Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 313:635-641.
50. Currie PJ, Khelemsky R, Rigsbee EM, Dono LM, Coiro CD, Chapman CD, Hinchcliff K (2012): Ghrelin is an orexigenic peptide and elicits anxiety-like behaviors following administration into discrete regions of the hypothalamus. Behav Brain Res 226:96-105.
51. Chuang JC, Perello M, Sakata I, Osborne-Lawrence S, Savitt JM, Lutter M, Zigman JM (2011): Ghrelin mediates stress-induced food-reward behavior in mice. J Clin Invest 121:2684-2692.
52. Walker AK, Rivera PD, Wang Q, Chuang JC, Tran S, Osborne-Lawrence S, et al. (2014): The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis [published online ahead of print April 22]. Mol Psychiatry; http://dxdoi.org/10.1038/mp. 2014.34.
53. 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.
54. Tang-Christensen M, Vrang N, Ortmann S, Bidlingmaier M, Horvath TL, Tschop M (2004): Central administration of ghrelin and agouti-related protein (83-132) increases food intake and decreases spontaneous locomotor activity in rats. Endocrinology 145:4645-4652.
55. Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA (2014): A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear. Mol Psychiatry 19:1284-1294.
56. Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, et al. (2012): Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 13:769-787.
57. Albarran-Zeckler RG, Brantley AF, Smith RG (2012): Growth hormone secretagogue receptor (GHS-R1a) knockout mice exhibit improved spatial memory and deficits in contextual memory. Behav Brain Res 232:13-19.
58. Andrews ZB (2011): The extra-hypothalamic actions of ghrelin on neuronal function. Trends Neurosci 34:31-40.
59. Stetler C, Miller GE (2011): Depression and hypothalamic-pituitary-adrenal activation: A quantitative summary of four decades of research. Psychosom Med 73:114-126.
60. Reppermund S, Zihl J, Lucae S, Horstmann S, Kloiber S, Holsboer F, Ising M (2007): Persistent cognitive impairment in depression: The role of psychopathology and altered hypothalamic-pituitary-adrenocortical (HPA) system regulation. Biol Psychiatry 62:400-406.
61. Holsboer F, Lauer CJ, Schreiber W, Krieg JC (1995): Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 62:340-347.
62. Lamers F, Vogelzangs N, Merikangas KR, De Jonge P, Beekman AT, Penninx BW (2013): Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry 18:692-699.
63. Gold PW, Chrousos GP (2002): Organization of the stress system and its dysregulation in melancholic and atypical depression: High vs low CRH/NE states. Mol Psychiatry 7:254-275.
64. Rao U (2013): Biomarkers in pediatric depression. Depress Anxiety 30:787-791.
65. Hansson C, Annerbrink K, Nilsson S, Bah J, Olsson M, Allgulander C, et al. (2013): A possible association between panic disorder and a polymorphism in the preproghrelingene. Psychiatry Res 206:22-25.
66. Barim AO, Aydin S, Colak R, Dag E, Deniz O, Sahin I (2009): Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment. Clin Biochem 42:1076-1081.
67. Ozsoy S, Besirli A, Abdulrezzak U, Basturk M (2014): Serum ghrelin and leptin levels in patients with depression and the effects of treatment. Psychiatry Investig 11:167-172.
68. Kurt E, Guler O, Serteser M, Cansel N, Ozbulut O, Altinbas K, et al. (2007): The effects of electroconvulsive therapy on ghrelin, leptin and cholesterol levels in patients with mood disorders. Neurosci Lett 426:49-53.
69. Kluge M, Schussler P, Schmid D, Uhr M, Kleyer S, Yassouridis A, Steiger A (2009): Ghrelin plasma levels are not altered in major depression. Neuropsychobiology 59:199-204.
70. Matsuo K, Nakano M, Nakashima M, Watanuki T, Egashira K, Matsubara T, Watanabe Y (2012): Neural correlates of plasma acylated ghrelin level in individuals with major depressive disorder. Brain Res 1473:185-192.
71. Schanze A, Reulbach U, Scheuchenzuber M, Groschl M, Kornhuber J, Kraus T (2008): Ghrelin and eating disturbances in psychiatric disorders. Neuropsychobiology 57:126-130.
72. Ishitobi Y, Kohno K, Kanehisa M, Inoue A, Imanaga J, Maruyama Y, et al. (2012): Serum ghrelin levels and the effects of antidepressants in major depressive disorder and panic disorder. Neuropsycho-biology 66:185-192.
73. Kluge M, Schussler P, Dresler M, Schmidt D, Yassouridis A, Uhr M, Steiger A (2011): Effects of ghrelin on psychopathology, sleep and secretion of cortisol and growth hormone in patients with major depression. J Psychiatr Res 45:421-426.
74. Hermans EJ, Henckens MJ, Joels M, Fernandez G (2014): Dynamic adaptation of large-scale brain networks in response to acute stressors. Trends Neurosci 37:304-314.
75. Pacak K, Palkovits M, Kopin IJ, Goldstein DS (1995): Stress-induced norepinephrine release in the hypothalamic paraventricular nucleus and pituitary-adrenocortical and sympathoadrenal activity: In vivo microdialysis studies. Front Neuroendocrinol 16:89-150.
76. Jansen AS, Schmidt ED, Voorn P, Tilders FJ (2003): Substance induced plasticity in noradrenergic innervation of the paraventricular hypothalamic nucleus. Eur J Neurosci 17:298-306.
77. Valentino RJ, Curtis AL, Page ME, Pavcovich LA, Florin-Lechner SM (1998): Activation of the locus ceruleus brain noradrenergic system during stress: Circuitry, consequences, and regulation. Adv Pharmacol 42:781-784.
78. Wittmann G (2008): Regulation of hypophysiotrophic corticotrophin-releasing hormone- and thyrotrophin-releasing hormone-synthesising neurones by brainstem catecholaminergic neurones. J Neuroendo-crinol 20:952-960.
79. Dunn AJ, Swiergiel AH, Palamarchouk V (2004): Brain circuits involved in corticotropin-releasing factor-norepinephrine interactions during stress. Ann NYAcad Sci 1018:25-34.
80. Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, et al. (2006): Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 116:3229-3239.
81. 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.
82. Lockie S, Andrews Z (2013): The hormonal signature of energy deficit: Increasing the value of food reward. Mol Metab 2:329-336.
83. Moon M, Kim S, Hwang L, Park S (2009): Ghrelin regulates hippo-campal neurogenesis in adult mice. Endocr J 56:525-531.
84. Legradi G, Hannibal J, Lechan RM (1998): Pituitary adenylate cyclase-activating polypeptide-nerve terminals densely innervate corticotropin-releasing hormone-neurons in the hypothalamic para-ventricular nucleus of the rat. Neurosci Lett 246:145-148.
85. Norrholm SD, Das M, Legradi G (2005): Behavioral effects of local microinfusion of pituitary adenylate cyclase activating polypeptide (PACAP) into the paraventricular nucleus of the hypothalamus (PVN). Regul Pept 128:33-41.
86. Das M, Vihlen CS, Legradi G (2007): Hypothalamic and brainstem sources of pituitary adenylate cyclase-activating polypeptide nerve fibers innervating the hypothalamic paraventricular nucleus in the rat. J Comp Neurol 500:761-776.
87. Kobelt P, Wisser AS, Stengel A, Goebel M, Inhoff T, Noetzel S, et al. (2008): Peripheral injection of ghrelin induces Fos expression in the dorsomedial hypothalamic nucleus in rats. Brain Res 1204:77-86.
88. Myers B, Mark Dolgas C, Kasckow J, Cullinan WE, Herman JP (2014): Central stress-integrative circuits: Forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Struct Funct 219:1287-1303.
89. Cullinan WE, Herman JP, Battaglia DF, Akil H, Watson SJ (1995): Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64:477-505.
90. Ziegler DR, Herman JP (2000): Local integration of glutamate signaling in the hypothalamic paraventricular region: Regulation of glucocorticoid stress responses. Endocrinology 141:4801-4804.
91. Bailey TW, Dimicco JA (2001): Chemical stimulation of the dorso-medial hypothalamus elevates plasma ACTH in conscious rats. Am J Physiol Regul Integr Comp Physiol 280:R8-R15.
92. Dayas CV, Buller KM, Crane JW, Xu Y, Day TA (2001): Stressor categorization: Acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci 14:1143-1152.
93. Dayas CV, Buller KM, Day TA (1999): Neuroendocrine responses to an emotional stressor: Evidence for involvement of the medial but not the central amygdala. Eur J Neurosci 11:2312-2322.
94. Joels M, Baram TZ (2009): The neuro-symphony of stress. Nat Rev Neurosci 10:459-466.
95. De Kloet ER, Joels M, Holsboer F (2005): Stress and the brain: From adaptation to disease. Nat Rev Neurosci 6:463-475.
96. Kozicz T, Bittencourt JC, May PJ, Reiner A, Gamlin PD, Palkovits M, et al. (2011): The Edinger-Westphal nucleus: A historical, structural, and functional perspective on a dichotomous terminology. J Comp Neurol 519:1413-1434.
97. Chuang JC, Zigman JM (2010): Ghrelin's roles in stress, mood, and anxiety regulation. Int J Pept 2010:460549; http://dx.doi.org/10.1155/2010/460549.
98. Tomiyama AJ, Dallman MF, Epel ES (2011): Comfort food is comforting to those most stressed: Evidence of the chronic stress response network in high stress women. Psychoneuroendocrinology 36:1513-1519.
99. Sarker MR, Franks S, Caffrey J (2013): Direction of post-prandial ghrelin response associated with cortisol response, perceived stress and anxiety, and self-reported coping and hunger in obese women. Behav Brain Res 257:197-200.
100. Jerlhag E, Egecioglu E, Landgren S, Salome N, Heilig M, Moechars D, et al. (2009): Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci USA 106:11318-11323.
101. 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.
102. Jerlhag E, Egecioglu E, Dickson SL, Engel JA (2010): Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomo-tor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacology (Berl) 211:415-422.
103. Wellman PJ, Clifford PS, Rodriguez J, Hughes S, Eitan S, Brunel L, et al. (2011): Pharmacologic antagonism of ghrelin receptors attenuates development of nicotine induced locomotor sensitization in rats. Regul Pept 172:77-80.
104. Wellman PJ, Hollas CN, Elliott AE (2008): Systemic ghrelin sensitizes cocaine-induced hyperlocomotion in rats. Regul Pept 146:33-37.
105. 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.
106. Clifford PS, Rodriguez J, Schul D, Hughes S, Kniffin T, Hart N, et al. (2012): Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors. Addict Biol 17:956-963.
107. Dickson SL, Hrabovszky E, Hansson C, Jerlhag E, Alvarez-Crespo M, Skibicka KP, et al. (2010): Blockade of central nicotine acetylcho-line receptor signaling attenuate ghrelin-induced food intake in rodents. Neuroscience 171:1180-1186.
108. 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.
109. Sinha R (2008): Chronic stress, drug use, and vulnerability to addiction. Ann NYAcad Sci 1141:105-130.
110. Kreek MJ, Nielsen DA, Butelman ER, La Forge KS (2005): Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 8:1450-1457.
111. 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.
112. Jiang H, Betancourt L, Smith RG (2006): Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol Endocrinol 20:1772-1785.
113. Kern A, Albarran-Zeckler R, Walsh HE, Smith RG (2012): Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 73:317-332.
114. Schellekens H, Dinan TG, Cryan JF (2013): Taking two to tango: A role for ghrelin receptor heterodimerization in stress and reward. Front Neurosci 7:148.
115. Schellekens H, Van Oeffelen WE, Dinan TG, Cryan JF (2013): Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling. J Biol Chem 288:181-191.
116. Delhanty PJ, Neggers SJ, Van Der Lely AJ (2013): Des-acyl ghrelin: A metabolically active peptide. Endocr Dev 25:112-121.
117. Delhanty PJ, Sun Y, Visser JA, Van Kerkwijk A, Huisman M, Van Ijcken WF, et al. (2010): Unacylated ghrelin rapidly modulates lipogenic and insulin signaling pathway gene expression in metabol-ically active tissues of GHSR deleted mice. PLoS One 5:e11749.
118. Zhao TJ, Liang G, Li RL, Xie X, Sleeman MW, Murphy AJ, et al. (2010): Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA 107:7467-7472.