Effects of the new ghrelin receptor antagonist agrelax on compulsive overeating induced by acute and chronic stress in rats

Abstract

BACKGROUND: Intense and prolonged stress can be detrimental to both psychological and physical health. Stress often leads to the development or worsening of compulsive overeating. Compulsive overeating is characterized by recurrent episodes of consuming large amounts of food, accompanied by a sense of loss of control.

AIM: To study the effects of the ghrelin receptor antagonist Agrelax on compulsive overeating induced by acute and chronic stress in rats.

MATERIALS AND METHODS: The study involved 150 male and 15 female Wistar rats. To simulate compulsive overeating, the animals received a high-calorie mixture based on chocolate paste three times a week, while maintaining free access to standard food and water. Compulsive behavior was assessed using the marble burying test. Different groups of animals were exposed to various stressors, including maternal deprivation, limb electrical stimulation, partial sensory and complete social isolation, and acute vital stress. Agrelax, a ghrelin receptor antagonist, was administered intranasally at a dose of 1 μg/μL, 10 μL in each nostril, for 7 days.

RESULTS: Compulsive behavior was evaluated using the marble burying test. The experimental group on a high-calorie diet buried significantly more marbles than the control group (p < 0.01). After a 7-day course of Agrelax, the number of buried marbles significantly decreased, reaching the control group values (p < 0.05). A model of compulsive overeating in rats was successfully developed by providing high-calorie food three times a week. After a 7-day course of Agrelax, the consumption of high-calorie food significantly decreased (p < 0.05). Limb electrical stimulation significantly increased the consumption of high-calorie food (p < 0.05). After a 7-day course of Agrelax, the consumption of high-calorie food significantly decreased (p < 0.01). Maternal deprivation stress significantly increased the consumption of high-calorie food (p < 0.001). After a 7-day course of Agrelax, the consumption of high-calorie food decreased, reaching the control group values. In animals raised under partial sensory and complete social isolation, Agrelax did not significantly reduce the consumption of high-calorie food. In animals subjected to acute vital stress, Agrelax did not reduce the consumption of high-calorie food.

CONCLUSIONS: The data obtained suggest new ways for synthesizing peptide pharmacological agents based on ghrelin and its antagonists to treat eating disorders.

Keywords

compulsive overeating / maternal deprivation / limb electrical stimulation / social isolation / vital stress / marble burying test / agrelax / ghrelin

References

[1] www.who.int [Internet]. Obesity and overweight, 2021 [cited: 21.04.2023]. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

[2] www.who.int [Электронный ресурс]. Obesity and overweight, 2021 [дата обращения: 21.04.2023]. Режим доступа: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

[3] Westbury S, Oyebode O, van Rens T, Barber TM. Obesity stigma: causes, consequences, and potential solutions. Curr Obes Rep. 2023;12(1):10–23. doi: 10.1007/s13679-023-00495-3

[4] Westbury S., Oyebode O., van Rens T., Barber T.M. Obesity stigma: causes, consequences, and potential solutions // Curr Obes Rep. 2023. Vol. 12, N 1. Р. 10–23. doi: 10.1007/s13679-023-00495-3

[5] Al-Sulaiti H, Diboun I, Agha MV, et al. Metabolic signature of obesity-associated insulin resistance and type 2 diabetes. J Transl Med. 2019;17(1):348. doi: 10.1186/s12967-019-2096-8

[6] Al-Sulaiti H., Diboun I., Agha M.V., et al. Metabolic signature of obesity-associated insulin resistance and type 2 diabetes // J Transl Med. 2019. Vol. 17, N 1. ID 348. doi: 10.1186/s12967-019-2096-8

[7] Avgerinos KI, Spyrou N, Mantzoros CS, Dalamaga M. Obesity and cancer risk: emerging biological mechanisms and perspectives. Metabolism. 2019;92:121–135. doi: 10.1016/j.metabol.2018.11.001

[8] Avgerinos K.I., Spyrou N., Mantzoros C.S., Dalamaga M. Obesity and cancer risk: emerging biological mechanisms and perspectives // Metabolism. 2019. Vol. 92. P. 121–135. doi: 10.1016/j.metabol.2018.11.001

[9] Lazzaroni E, Ben Nasr M, Loretelli C, et al. Anti-diabetic drugs and weight loss in patients with type 2 diabetes. Pharm Res. 2021;171:105782. doi: 10.1016/j.phrs.2021.105782

[10] Lazzaroni E., Ben Nasr M., Loretelli C., et al. Anti-diabetic drugs and weight loss in patients with type 2 diabetes // Pharm Res. 2021. Vol. 171. ID 105782. doi: 10.1016/j.phrs.2021.105782

[11] Powell-Wiley TM, Poirier P, Burke LE, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143(21):e984–e1010. doi: 10.1161/CIR.0000000000000973

[12] Powell-Wiley T.M., Poirier P., Burke L.E., et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association // Circulation. 2021. Vol. 143, N 21. P. e984–e1010. doi: 10.1161/CIR.0000000000000973

[13] Shah MS, Patel ZK, Bharucha R, et al. Sibutramine-induced nonischemic cardiomyopathy. Cureus. 2022;14(1):e21650. doi: 10.7759/cureus.21650

[14] Shah M.S., Patel Z.K., Bharucha R., et al. Sibutramine-induced nonischemic cardiomyopathy // Cureus. 2022. Vol. 14, N 1. ID e21650. doi: 10.7759/cureus.21650

[15] Nguyen T, Thomas BF, Zhang Y. Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: current approaches for therapeutics development. Curr Top Med Chem. 2019;19(16):1418–1435. doi: 10.2174/1568026619666190708164841

[16] Nguyen T., Thomas B.F., Zhang Y. Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: current approaches for therapeutics development // Curr Top Med Chem. 2019. Vol. 19, N 16. P. 1418–1435. doi: 10.2174/1568026619666190708164841

[17] Filippatos TD, Derdemezis CS, Gazi IF, et al. Orlistat-associated adverse effects and drug interactions: a critical review. Drug Saf. 2008;31(1):53–65. doi: 10.2165/00002018-200831010-00005

[18] Filippatos T.D., Derdemezis C.S., Gazi I.F., et al. Orlistat-associated adverse effects and drug interactions: a critical review // Drug Saf. 2008. Vol. 31, N 1. P. 53–65. doi: 10.2165/00002018-200831010-00005

[19] Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281(3):235–242. doi: 10.1001/jama.281.3.235

[20] Davidson M.H., Hauptman J., DiGirolamo M., et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial // JAMA. 1999. Vol. 281, N 3. P. 235–242. doi: 10.1001/jama.281.3.235

[21] O’Meara S, Riemsma R, Shirran L. A systematic review of the clinical effectiveness of orlistat used for the management of obesity. Obes Rev. 2004;5(1):51–68. doi: 10.1111/j.1467-789X.2004.00125.x

[22] O’Meara S., Riemsma R., Shirran L. A systematic review of the clinical effectiveness of orlistat used for the management of obesity // Obes Rev. 2004. Vol. 5, N 1. P. 51–68. doi: 10.1111/j.1467-789X.2004.00125.x

[23] US Food and drug [Internet]. Administration, FDA approves new drug treatment for chronic weight management, first since 2014, 2021 [cited: 21.04.2023]. Available from: https://www.fda.gov/news-event s/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014

[24] US Food and drug [Электронный ресурс]. Administration, FDA approves new drug treatment for chronic weight management, first since 2014, 2021 [дата обращения: 21.04.2023]. Режим доступа: https://www.fda.gov/news-event s/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014

[25] Beck B, Fernette B, StrickerKrongrad A. Peptide S is a novel potent inhibitor of voluntary and fast-induced food intake in rats. Biochem Biophys Res Commun. 2005;332(3):859–865. doi: 10.1016/j.bbrc.2005.05.029

[26] Beck B., Fernette B., StrickerKrongrad A. Peptide S is a novel potent inhibitor of voluntary and fast-induced food intake in rats // Biochem Biophys Res Commun. 2005. Vol. 332, N 3. P. 859–865. doi: 10.1016/j.bbrc.2005.05.029

[27] Zhang J, Ren P, Avsian-Kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science. 2005;310(5750):996–999. doi: 10.1126/science.1117255

[28] Zhang J., Ren P., Avsian-Kretchmer O., et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake // Science. 2005. Vol. 310, N 5750. P. 996–999. doi: 10.1126/science.1117255

[29] Chen CY, Asakawa M, Fujimiya M, et al. Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev. 2009;61(4):430–481. doi: 10.1124/pr.109.001958

[30] Chen C.Y., Asakawa M., Fujimiya M., et al. Ghrelin gene products and the regulation of food intake and gut motility // Pharmacol Rev. 2009. Vol. 61, N 4. P. 430–481. doi: 10.1124/pr.109.001958

[31] Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metabolism. 2002;87:2988. doi: 10.1210/jcem.87.6.8739

[32] Gnanapavan S., Kola B., Bustin S.A., et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans // J Clin Endocrinol Metabolism. 2002. Vol. 87. ID 2988. doi: 10.1210/jcem.87.6.8739

[33] Lebedev AA, Karpova IV, Bychkov ER, et al. The ghrelin antagonist [D-LYS3]-GHRP-6 decreases signs of risk behavior in a model of gambling addiction in rats by altering dopamine and serotonin metabolism. Neurosci Behav Physiol. 2022;52(3):415–421. doi: 10.19163/MedChemRussia2021-2021-259

[34] Lebedev A.A., Karpova I.V., Bychkov E.R., et al. The ghrelin antagonist [D-LYS3]-GHRP-6 decreases signs of risk behavior in a model of gambling addiction in rats by altering dopamine and serotonin metabolism // Neurosci Behav Physiol. 2022. Vol. 52, N 3. P. 415–421. doi: 10.19163/MedChemRussia2021-2021-259

[35] Nass R, Pezzoli SS, Oliveriet MC, al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: A randomized trial. Ann Intern Med. 2008;149(9):601– 611 doi: 10.7326/0003-4819-149-9-200811040-00003

[36] Nass R., Pezzoli S.S., Oliveriet M.C., al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: A randomized trial // Ann Intern Med. 2008. Vol. 149, N 9. P. 601–611. doi: 10.7326/0003-4819-149-9-200811040-00003

[37] Huda MSB, Dovey T, Wong SP, et al. Ghrelin restores “lean-type” hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects. Int J Obes. 2009;33(3):317–325. doi: 10.1038/ijo.2008.270

[38] Huda M.S.B., Dovey T., Wong S.P., et al. Ghrelin restores “lean-type” hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects // Int J Obes. 2009. Vol. 33, N 3. P. 317–325. doi: 10.1038/ijo.2008.270

[39] Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural gh secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab. 2001;86(10):5083–5086. doi: 10.1210/jcem.86.10.8098

[40] Broglio F., Arvat E., Benso A., et al. Ghrelin, a natural gh secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans // J Clin Endocrinol Metab. 2001. Vol. 86, N 10. P.5083–5086. doi: 10.1210/jcem.86.10.8098

[41] Reimer MK. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology. 2003;144(3):916–921. doi: 10.1210/en.2002-220819

[42] Reimer M.K. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse // Endocrinology. 2003. Vol. 144, N 3. P. 916–921. doi: 10.1210/en.2002-220819

[43] Ducharme R, Anisman H, Abizaid A. Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor-deficient mice. Eur J Neurosci. 2010;32(4):632–639. doi: 10.1111/j.1460-9568.2010.07310.x

[44] Ducharme R., Anisman H., Abizaid A. Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor-deficient mice // Eur J Neurosci. 2010. Vol. 32, N 4. P. 632–639. doi: 10.1111/j.1460-9568.2010.07310.x

[45] Johnson PM, Kenny PJ. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci. 2010;13(5):635–641. doi: 10.1038/nn.2519

[46] Johnson P.M., Kenny P.J. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats // Nat Neurosci. 2010. Vol. 13, N 5. P. 635–641. doi: 10.1038/nn.2519

[47] Association AP. Diagnostic and statistical manual of mental disorders: DSM-5-TR. Washington; London, 2013.

[48] Association A.P. Diagnostic and statistical manual of mental disorders: DSM-5-TR. Washington; London, 2013.

[49] Lenoir M, Serre F, Cantin L, Ahmed SH. Intense sweetness surpasses cocaine reward. PLoS ONE. 2007;2(8):e698. doi: 10.1371/journal.pone.0000698

[50] Lenoir M., Serre F., Cantin L., Ahmed S.H. Intense sweetness surpasses cocaine reward // PLoS ONE. 2007. Vol. 2, N 8. ID e698. doi: 10.1371/journal.pone.0000698

[51] Heo Y-A, Duggan ST. Lisdexamfetamine: a review in binge eating disorder. CNS Drugs. 2017;31(11):1015–1022. doi: 10.1007/s40263-017-0477-1

[52] Heo Y.-A., Duggan S.T. Lisdexamfetamine: a review in binge eating disorder // CNS Drugs. 2017. Vol. 31, N 11. P. 1015–1022. doi: 10.1007/s40263-017-0477-1

[53] Ward K, Citrome L. Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder. Expert Opin Drug Metab Toxicol. 2018;14(2):229–238. doi: 10.1080/17425255.2018.1420163

[54] Ward K., Citrome L. Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder // Expert Opin Drug Metab Toxicol. 2018. Vol. 14, N 2. Р. 229–238. doi: 10.1080/17425255.2018.1420163

[55] Boggiano MM, Artiga AI, Pritchett CE, et al. High intake of palatable food predicts binge-eating independent of susceptibility to obesity: An animal model of lean vs obese binge-eating and obesity with and without binge-eating. Int J Obes. 2007;31(9):1357–1367. doi: 10.1038/sj.ijo.0803614

[56] Boggiano M.M., Artiga A.I., Pritchett C.E., et al. High intake of palatable food predicts binge-eating independent of susceptibility to obesity: An animal model of lean vs obese binge-eating and obesity with and without binge-eating // Int J Obes. 2007. Vol. 31, N 9. P. 1357–1367. doi: 10.1038/sj.ijo.0803614

[57] Corwin RL, Wojnicki FHE. Binge eating in rats with limited access to vegetable shortening. Curr Protoc Neurosci. 2006;36:9.23B.1–9.23B.11. doi. 10.1002/0471142301.ns0923bs36

[58] Corwin R.L., Wojnicki F.H.E. Binge eating in rats with limited access to vegetable shortening // Curr Protoc Neurosci. 2006. Vol. 36. P. 9.23B.1–9.23B.11. doi. 10.1002/0471142301.ns0923bs36

[59] Moore CF, Leonard MZ, Micovic NM, et al. Reward sensitivity deficits in a rat model of compulsive eating behavior. Neuropsychopharmacol. 2020;45:589–596 doi: 10.1038/s41386-019-0550-1

[60] Moore C.F., Leonard M.Z., Micovic N.M., et al. Reward sensitivity deficits in a rat model of compulsive eating behavior // Neuropsychopharmacol. 2020. Vol. 45. P. 589–596 doi: 10.1038/s41386-019-0550-1

[61] Ushakov IB, Bubeev YuA, Krasovets SV, Ivanov AV. Individual psychophysiological mechanisms of adaptation under stress of lethal situations. Neuroscience and Behavioral Physiology. 2012;98(1):83–94. EDN: OXHHIZ (In Russ.)

[62] Ушаков И.Б., Бубеев Ю.А., Красовец С.В., Иванов А.В. Индивидуальные психофизиологические механизмы адаптации при стрессе смертельно опасных ситуаций // Российский физиологический журнал им. И.М. Сеченова. 2012. Т. 98, № 1. C. 83–94. EDN: OXHHIZ

[63] Evdokimov VI, Shamrey VK, Pluzhnik MS. Combat stress research prospects in Russian academic publications analyzed using to VOSviewer software (2005–2021). Medicо-Biological and Socio-Psychological Problems of Safety in Emergency Situations. 2023;(2):99–116. EDN: RUXCZT doi: 10.25016/2541-7487-2023-0-2-99-116

[64] Евдокимов В.И., Шамрей В.К., Плужник М.С. Развитие направлений научных исследований по боевому стрессу в отечественных статьях с использованием программы vosviewer (2005–2021 гг.) // Медико-биологические и социально-психологические проблемы безопасности в чрезвычайных ситуациях. 2023. № 2. C. 99–115. EDN: RUXCZT doi: 10.25016/2541-7487-2023-0-2-99-116

[65] Sayin Kasar K, Karaman E. Life in lockdown: Social isolation, loneliness and quality of life in the elderly during the COVID-19 pandemic: A scoping review. Geriatr Nurs. 2021;42(5):1222–1229. doi: 10.1016/j.gerinurse.2021.03.010

[66] Sayin Kasar K., Karaman E. Life in lockdown: Social isolation, loneliness and quality of life in the elderly during the COVID-19 pandemic: A scoping review // Geriatr Nurs. 2021. Vol. 42, N 5. Р. 1222–1229. doi: 10.1016/j.gerinurse.2021.03.010

[67] DiLeone RJ, Georgescu D, Nestler EJ. Lateral hypothalamic neuropeptides in reward and drug addiction. Life Sci. 2003;73(6):759–768. doi: 10.1016/s0024-3205(03)00408-9

[68] DiLeone R.J., Georgescu D., Nestler E.J. Lateral hypothalamic neuropeptides in reward and drug addiction // Life Sci. 2003. Vol. 73, N 6. P. 759–768. doi: 10.1016/s0024-3205(03)00408-9

[69] Lutter M, Nestler EJ. Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr. 2009;139(3):629–632. doi: 10.3945/jn.108.097618

[70] Lutter M., Nestler E.J. Homeostatic and hedonic signals interact in the regulation of food intake // J Nutr. 2009. Vol. 139, N 3. P. 629–632. doi: 10.3945/jn.108.097618

[71] Colantuoni C, Schwenker J, McCarthy J, et al. Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. Neuroreport. 2001;12(16):3549–3552. doi: 10.1097/00001756-200111160-00035

[72] Colantuoni C., Schwenker J., McCarthy J., et al. Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain // Neuroreport. 2001. Vol. 12, N 16. P. 3549–3552. doi: 10.1097/00001756-200111160-00035

[73] Lebedev AА, Pyurveev SS, Nadbitova ND, et al. Reduction of compulsive overeating in rats caused by maternal deprivation in early ontogenesis with the use of a new ghrelin receptor antagonist agrelax. Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(3):255–262. EDN: SLBOTQ doi: 10.17816/RCF562841

[74] Лебедев А.А., Пюрвеев С.С., Надбитова Н.Д., и др. Снижение компульсивного переедания у крыс, вызванного материнской депривацией в раннем отногенезе, с применением нового антагониста рецепторов грелина агрелакс // Обзоры по клинической фармакологии и лекарственной терапии. 2023. Т. 21, № 3. C. 255–262. EDN: SLBOTQ doi: 10.17816/RCF562841

[75] Shabanov PD, Lebedev AA, Rusanovsky BB, Streltsov VF. Behavioral effects of corticoliberin and its analogs injected into rat brain ventricles. Medical academic journal. 2005;5(3):59–67. EDN: VLHVOZ (In Russ.)

[76] Шабанов П.Д., Лебедев А.А., Русановский В.В., Стрельцов В.Ф. Поведенческие эффекты кортиколиберина и его аналогов, вводимых в желудочки мозга крыс // Медицинский академический журнал. 2005. Т. 5, № 3. С. 59–67. EDN: VLHVOZ

[77] Piccoli L, Micioni Di Bonaventura MV, Cifani C, et al. Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats. Neuropsychopharmacology. 2012;37(9):1999–2011. doi: 10.1038/npp.2012.48

[78] Piccoli L., Micioni Di Bonaventura M.V., Cifani C., et al. Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats // Neuropsychopharmacology. 2012. Vol. 37, N 9. P. 1999–2011. doi: 10.1038/npp.2012.48

[79] Craft RM, Howard JL, Pollard GT. Conditioned defensive burying as a model for identifying anxiolytics. Pharmacol Biochem Behav. 1988;30(3):775–780. doi: 10.1016/0091-3057(88)90098-6

[80] Craft R.M., Howard J.L., Pollard G.T. Conditioned defensive burying as a model for identifying anxiolytics // Pharmacol Biochem Behav. 1988. Vol. 30, N 3. P. 775–780. doi: 10.1016/0091-3057(88)90098-6

[81] Kalinina T, Kudryashov N, Naplekova P, et al. P.1.h.032 Interaction of antidepressants with mild chronic stress: behavioural effects and content of monoamines and their metabolites in mouse brain. Eur Neuropsychopharmacol. 2014;24:288. doi: 10.1016/s0924-977x(14)70455-9

[82] Kalinina T., Kudryashov N., Naplekova P., et al. P.1.h.032 Interaction of antidepressants with mild chronic stress: behavioural effects and content of monoamines and their metabolites in mouse brain // Eur Neuropsychopharmacol. 2014. Vol. 24. ID 288. doi: 10.1016/s0924-977x(14)70455-9

[83] Naumenko VS, Bazovkina DV, Semenova AA, et al. Effect of glial cell line-derived neurotrophic factor on behaviorand key members of the brain serotonin system in mouse strains genetically predisposed to behavioral disorders. J Neurosci Res. 2013;91(12):1628–1638. doi: 10.1002/jnr.23286

[84] Naumenko V.S., Bazovkina D.V., Semenova A.A., et al. Effect of glial cell line-derived neurotrophic factor on behaviorand key members of the brain serotonin system in mouse strains genetically predisposed to behavioral disorders // J Neurosci Res. 2013. Vol. 91, N 12. P. 1628–1638. doi: 10.1002/jnr.23286

[85] Bali A, Jaggi AS. Electric foot shock stress: A useful tool in neuropsychiatric studies. Rev Neurosci. 2015;26(6):655–677. doi: 10.1515/revneuro-2015-0015

[86] Bali A., Jaggi A.S. Electric foot shock stress: A useful tool in neuropsychiatric studies // Rev Neurosci. 2015. Vol. 26, N 6. P. 655–677. doi: 10.1515/revneuro-2015-0015

[87] Tsikunov SG, Klyueva NN, Kusov AG, et al. Changes in the lipid composition of blood plasma and liver in rats induced by severe psychic trauma. Bulletin of Experimental Biology and Medicine. 2006;141(5):575–578. EDN: HTPYLD

[88] Цикунов С.Г., Клюева Н.Н., Кусов А.Г., и др. Изменение липидного спектра сыворотки крови и печени крыс, вызванное тяжелой психогенной травмой // Бюллетень экспериментальной биологии и медицины. 2006. Т. 141, № 5. С. 575–578. EDN: HTPYLD

[89] Yakushina ND, Tissen IYu, Lebedev AA, et al. Effect of intranasal ghrelin administration on the compulsive behavior patterns and the level of anxiety after the vital stress exposure to rats. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):28–37. EDN: ZHRRKX doi: 10.17816/RCF15328-37

[90] Якушина Н.Д., Тиссен И.Ю., Лебедев А.А., и др. Влияние интраназально вводимого грелина на проявления компульсивного поведения и уровень тревожности у крыс после витального стрессорного воздействия // Обзоры по клинической фармакологии и лекарственной терапии. 2017. Т. 15, № 3. C. 28–37. EDN: ZHRRKX doi: 10.17816/RCF15328-37

[91] Veale D, Roberts A. Obsessive-compulsive disorder. Biomed J. 2014;348:2183. doi: 10.1136/bmj.g2183

[92] Veale D., Roberts A. Obsessive-compulsive disorder // Biomed J. 2014. Vol. 348. ID 2183. doi: 10.1136/bmj.g2183

[93] Decloedt EH, Stein DJ. Current trends in drug treatment of obsessive-compulsive disorder. Neuropsychiatr Dis Treat. 2010;6(1):233–242. doi: 10.2147/NDT.S3149

[94] Decloedt E.H., Stein D.J. Current trends in drug treatment of obsessive-compulsive disorder // Neuropsychiatr Dis Treat. 2010. Vol. 6, N 1. P. 233–242. doi: 10.2147/NDT.S3149

[95] Koob GF. Dynamics of neuronal circuits in addiction: reward, antireward and emotional memory. Pharmacopsychiatry. 2009;42(10):32–41. doi: 10.1055/s-0029-1216356

[96] Koob G.F. Dynamics of neuronal circuits in addiction: reward, antireward and emotional memory // Pharmacopsychiatry. 2009. Vol. 42, N 10. P. 32–41. doi: 10.1055/s-0029-1216356

[97] Shabanov PD, Lebedev AA, Yakushina ND, et al. Modeling the obsessive-compulsive and addictive gambling behavior in a rat marble test by means of amphetamine administration. Narcology. 2017;16(1):32–38. EDN: XWNOMF

[98] Шабанов П.Д., Лебедев А.А., Якушина Н.Д., и др. Моделирование обсессивно-компульсивного и аддиктивного игрового поведения у крыс введением фенамина в тесте закапывания шариков // Наркология. 2017. Т. 16, № 1. С. 32–38. EDN: XWNOMF

[99] Shabanov PD, Lebedev AA, Yakushina ND, et al. Effect of amphetamine on behavioral patterns of obsessive-compulsive and addictive gambling in a rat marble test. Reviews on Clinical Pharmacology and Drug Therapy. 2016;14(3):46–52. EDN: WWUKGT doi: 10.17816/RCF14346-52

[100] Шабанов П.Д., Лебедев А.А., Якушина Н.Д., и др. Влияние фенамина на поведенческие компоненты обсессивно-компульсивного и аддиктивного игрового поведения в тесте закапывания шариков у крыс // Обзоры по клинической фармакологии и лекарственной терапии. 2016. Т. 14, № 3. С. 46–52. EDN: WWUKGT doi: 10.17816/RCF14346-52

[101] Shabanov PD, Yakushina ND, Lebedev AA. Pharmacology of peptide mechanisms of gambling behavior in rats. Journal of addiction problems. 2020;(4):24–44. EDN: JBUQJN doi: 10.47877/0234-0623_2020_4_24

[102] Шабанов П.Д., Якушина Н.Д., Лебедев А.А. Фармакология пептидных механизмов игрового поведения у крыс // Вопросы наркологии. 2020. № 4. С. 24–44. EDN: JBUQJN doi: 10.47877/0234-0623_2020_4_24

[103] Geliebter A, Marci EG, Sami AH. Plasma ghrelin concentrations are lower in binge-eating disorder. J Nutr. 2005;135(5):1326–1330. doi: 10.1093/jn/135.5.1326

[104] Geliebter A., Marci E.G., Sami A.H. Plasma ghrelin concentrations are lower in binge-eating disorder // J Nutr. 2005. Vol. 135, N 5. P. 1326–1330. doi: 10.1093/jn/135.5.1326

[105] Alvarez-Crespo M, Skibicka KP, Farkas I, et al. The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence. PloS one. 2012;7(10):e46321. doi: 10.1371/journal.pone.0046321

[106] Alvarez-Crespo M., Skibicka K.P., Farkas I., et al. The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence // PloS one. 2012. Vol. 7, N 10. ID e46321. doi: 10.1371/journal.pone.0046321

[107] Carroll ME, France CP, Meisch RA, at al. Food deprivation increases oral and intravenous drug intake in rats. Science (New York). 1979;205(4403):319–321. doi: 10.1126/science.36665

[108] Carroll M.E., France C.P., Meisch R.A., at al. Food deprivation increases oral and intravenous drug intake in rats // Science (New York).1979. Vol. 205, N 4403. P. 319–321. doi: 10.1126/science.36665

[109] Kharbanda KK, Farokhnia M, Deschaine SL, at al. Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease. A narrative review. Alcohol Clin Exp Res. 2022;46(12):2149–2159. doi: 10.1111/acer.14967

[110] Kharbanda K.K., Farokhnia M., Deschaine S.L., at al. Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease. A narrative review // Alcohol Clin Exp Res. 2022. Vol. 46, N 12. P. 2149–2159. doi: 10.1111/acer.14967

[111] Goeders NE. The impact of stress on addiction. Eur Neuropsychopharmacol. 2003;13(6):435–441. doi: 10.1016/j.euroneuro.2003.08.004

[112] Goeders N.E. The impact of stress on addiction // Eur Neuropsychopharmacol. 2003. Vol. 13, N 6. P. 435–441. doi: 10.1016/j.euroneuro.2003.08.004

Funding

Министерство науки и высшего образования РФ (проект)Ministry of Science and Higher Education of the Russian Federation (project)(FGWG-2022-0004)

RIGHTS & PERMISSIONS

Eco-Vector