[D-Lys 3]-GHRP-6, an antagonist of ghrelin receptors, decreases expression of conditioned place preference reaction of ethanol in rats

Abstract

Ghrelin is a peptide hormone synthesized and secreted by the stomach into the bloodstream. The greatest attention of neuroscience research is devoted to investigation of acylated form of ghrelin, which is a specific ligand for the receptor subcortical nuclei of the brain. The aim of this study was to analyze the action of ghrelin and its antagonist on the expression of conditioned place preference (СPP) of ethanol. To develop CPP of alcohol we used a two-chamber apparatus. Rats were spent 74 % of time experiment in chamber associated with alcohol. Rats receiving intranasal receptor ghrelin antagonist [D-Lys3]-GHRP-6 (10 µg) reduced the time of staying in the chamber associated with alcohol for 46 % (p < 0.05). Rats treated with intranasal ghrelin spent in the chamber, associated with alcohol, for 60 % of time. Then the extinction of CPP was produced when rats was replaced into the apparatus every day for 7 days without administration alcohol or any substances. On the 7th day of extinction, CPP was not reproduced. But after administration of ethanol on the 7th day CPP was reinstated. Animals received GHS-R1A receptor ghrelin antagonist [D-Lys3]-GHRP-6 (10 µg) and ethanol spent 50 % of time in chamber associated with the administration of ethanol, i.e. CPP was not reinstated. Animals treated with ghrelin, demonstrated a range of reactions from a sharp preference to avoidance of the place associated with ethanol. Thus, the present study shows the important role of ghrelin in the mechanisms of the reinforcing effects of alcohol and demonstrates the prospect for using of ghrelin antagonists in the correction of pathological craving in addictive disordes.

Keywords

ghrelin / [D-Lys ]-GHRP-6 / the conditional place preference response / reinforcement / emotions

References

[1] Шабанов П. Д. Психофармакология. СПб.: Н-Л, 2008. 384 с.

[2] Шабанов П. Д., Лебедев А. А. Угнетение самостимуляции латерального гипоталамуса опиатами и опиоидами, вводимыми в центральное ядро миндалины у крыс. Рос. физиол. журн. им. И. М. Сеченова. 2010; 97 (2): 180-8.

[3] Шабанов П. Д., Лебедев А. А., Мещеров Ш. К. Дофамин и подкрепляющие системы мозга. СПб.: Лань, 2002. 208 с.

[4] Шабанов П. Д., Лебедев А. А., Стрельцов В. Ф. Гормональные механизмы подкрепления. СПб.: Н-Л, 2008. 208 с.

[5] Шабанов П. Д., Сапронов Н. С. Психонейроэндокринология. СПб.: Информ-Навигатор, 2010. 984 с.

[6] Asakawa A., Inui A., Kaga T., Katsuura G., Fujimiya M., Fujino M. A., Kasuga M. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut. 2003; 52: 947-52.

[7] Asakawa A., Inui A., Kaga T., Yuzuriha H., Nagata T., Ueno N., Makino S., Fujimiya M., Niijima A., Fujino M. A., Kasuga M. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterol. 2001; 120 (2): 337-45.

[8] Cowley M. A., Smith R. G., Diano S., Tschop M., Pronchuk N., Grove K. L., Strasburger C. J., Bidlingmaier M., Esterman M., Heiman M. L., Garcia-Segura L. M., Nillni E. A., Mendez P., Low M. J., Sotonyi P., Friedman J. M., Liu H., Pinto S., Colmers W. F., Cone R. D., Horvath T. L. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003; 37: 649-61.

[9] Cummings D. E., Clement K., Purnell J. Q., Vaisse C., Foster K. E., Frayo R. S., Schwartz M. W., Basdevant A., Weigle D. S. Elevated plasma ghrelin levels in Prader-Willi syndrome. Nature. 2002; 8 (7): 643-4.

[10] Cummings D. E., Frayo, R. S., Marmonier C., Aubert R., Chapelot D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Amer. J. Physiol. Endocrinol. and Metab. 2004; 287 (2): E297-E304.

[11] Cummings D. E., Purnell J. Q., Frayo R. S., Schmidova K., Wisse B. E., Weigle D. S. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001; 50 (8): 1714-9.

[12] Dickson S. L., Egecioglu E., Landgren S., Skibicka K. P., Engel J. A., Jerlhag E. The role of the central ghrelin system in reward from food and chemical drugs. Mol. Cell Endocrinol. 2011; 340: 80-7.

[13] Dickson S. L., Hrabovszky E., Hansson C., Jerlhag E., Alvarez-Crespo M., Skibicka K. P., Molnar C. S., Liposits Z., Engel J. A., Egecioglu E. Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents. Neuroscience. 2010; 171 (4): 1180-6.

[14] Dickson S. L., Leng G., Robinson I. C. Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons. Neuroscience. 1993; 53 (2): 303-6.

[15] Dickson S. L., Luckman S. M. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GHreleasing peptide-6. Endocrinology. 1997; 138 (2): 771-7.

[16] Egecioglu E., Jerlhag E., Salome N., Skibicka K. P., Haage D., Bohlooly Y. M., Andersson D., Bjursell M., Perrissoud D., Engel J. A., Dickson S. L. Ghrelin increases intake of rewarding food in rodents. Addict. Biol. 2010; 15(3): 304-11.

[17] Egecioglu E., Skibicka K. P., Hansson C., Alvarez-Crespo M., Friberg A., Jerlhag E., Engel J. A., Dickson S. L. Hedonic and incentive signals for body weight control. Rev. Endocrinol. Metab. Disor. (Epub ahead of print). doi:10.1007/s11154-011-9166-4.

[18] Gualillo O., Caminos J. E., Nogueiras R., Seoane L. M., Arvat E., Ghigo E., Casanueva F. F., Dieguez C. Effect of food restriction on ghrelin in normal-cycling female rats and in pregnancy. Obesity Res. 2002; 10 (7): 682-7.

[19] Jerlhag E. Systemic administration of ghrelin induces conditioned place preference and stimulates accumbal dopamine. Addic. Biol. 2008; 13: 3-4.

[20] Jerlhag E., Egecioglu E., Dickson S. L., Andersson M., Svensson L., Engel J. A. Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addic. Biol. 2006; 11 (1): 45-54.

[21] Jerlhag E., Egecioglu E., Dickson S. L., Douhan A., Svensson L., Engel J. A. Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addic. Biol. 2007; 12 (1): 6-16.

[22] Jerlhag E., Egecioglu E., Dickson S. L., Engel J. A. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacol. (Berl.) 2010; 211 (4): 415-22.

[23] Jerlhag E., Egecioglu E., Dickson S. L., Engel J. A. Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system. Addic. Biol. 2011; 16 (1): 82-91.

[24] Jerlhag E., Egecioglu E., Dickson S. L., Svensson L., Engel J. A. Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens. Eur. Neuropsychopharmacol. 2008; 18 (7): 508-18.

[25] Jerlhag E., Egecioglu E., Landgren S., Salome N., Heilig M., Moechars D., Datta, R., Perrissoud D., Dickson S. L., Engel J. A. Requirement of central ghrelin signaling for alcohol reward. Proc. Nat. Acad. Sci. USA. 2009; 106 (27): 11318-23.

[26] Jerlhag E., Grotli M., Luthman K., Svensson L., Engel J. A. Role of the subunit composition of central nicotinic acetylcholine receptors for the stimulatory and dopamine-enhancing effects of ethanol. Alcohol Alcoholism. 2006; 41 (5): 486-93.

[27] Jerlhag E., Landgren S., Egecioglu E., Dickson S. L., Engel J. A. The alcohol induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice. Alcohol. (Epub ahead of print) doi:10.1016/j.alcohol.2010.10.002.

[28] Kaur S., Ryabinin A. E. Ghrelin receptor antagonism decreases alcohol consumption and activation of perioculomotor urocortin-containing neurons. Alcohol Clin. Exp. Res. 2010; 34 (9): 1525-34.

[29] Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999; 402 (6762): 656-60.

[30] Lall S., Tung L. Y. C., Ohlsson C., Jansson J. O., Dickson S. L. Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues. Biochem. Biophys. Res. Com. 2001; 280 (1): 132-8.

[31] Lyons A. M., Lowery E. G., Sparta D. R., Thiele T. E. 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. 2008; 32 (11): 1962-8.

[32] Olszewski P. K., Grace M. K., Billington C. J., Levine A. S. Hypothalamic paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity. Peptides. 2003; 24 (6): 919-23.

[33] Olszewski P. K., Li D. H., Grace M. K., Billington C. J., Kotz C. M., Levine A. S., Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus. Peptides. 2003; 24 (4): 597-602.

[34] Perello M., Sakata I., Birnbaum S., Chuang J. C., Osborne-Lawrence, S., Rovinsky S. A., Woloszyn J., Yanagisawa M., Lutter M., Zigman J. M. Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol. Psychiatry. 2010; 67 (9): 880-6.

[35] Rauh M, Groschl M, Rascher W. Simultaneous quantification of ghrelin and desacyl-ghrelin by liquid chromatography-tandem mass spectrometry in plasma, serum, and cell supernatants. Clin. Chemistry. 2007; 53 (5): 902-10.

[36] Tschop M., Smiley D. L., Heiman M. L. Ghrelin induces adiposity in rodents. Nature. 2000; 407 (6806): 908-13.

[37] Tschop M., Wawarta R., Riepl R. L., Friedrich S., Bidlingmaier M., Landgraf R., Folwaczny C. Post-prandial decrease of circulating human ghrelin levels. J. Endocrinol. Invest. 2001; 24 (6): Rc19-Rc21.

[38] Wren A. M., Seal L. J., Cohen M. A., Brynes A. E., Frost G. S., Murphy K. G., Dhillo W. S., Ghatei M. A., Bloom S. R. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Met. 2001; 86 (12): 5992-5.

[39] Wren A. M., Small C. J., Abbott C. R., Dhillo W. S., Seal L. J., Cohen M. A., Batterham R. L., Taheri S., Stanley S. A., Ghatei M. A., Bloom S. R. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 2001; 50 (11): 2540-7.

[40] Wren A. M., Small C. J., Ward H. L., Murphy K. G., Dakin C. L., Taheri S., Kennedy A. R., Roberts G. H., Morgan D. G. A., Ghatei M. A., Bloom S. R. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinol. 2000; 141 (11): 4325-8.

RIGHTS & PERMISSIONS

Vinogradov P.M., Tissen I.Y., Lebedev A.A., Bychkov E.R., Lavrov N.V., Botkin E.A., Shabanov P.D.