Correction of compulsive overeating in rats after maternal deprivation in early age using a new antagonist of OX1 receptors

Abstract

BACKGROUND: Compulsive overeating (bulimia nervosa, binge eating disorder) is the basis of eating disorders and is included in ICD-11 and DSM-5 as a manifestation of nonchemicaladdiction and a behavioral disorder of impulsivity and compulsivity. Obesity and eating disorders are characterized by compulsive food consumption, similar to compulsive drug use in substance use disorders. AIM: To evaluate the effect of the OX1 receptor antagonist anthorex on compulsive overeating in animals in a maternal deprivation model. MATERIALS AND METHODS: Sexually mature male rats, which were separated from their mother for 3 h after birth from days 2 to 12, were fed a high-carbohydrate diet every third day for 1 h for 45 days. High-calorie food was placed within 5 cm of reach with visual contact 15 minutes before feeding. Anthorex was administered intranasally for 7 days at a dose of 1 µg/1 µl, 20 µl. RESULTS: Intermittent consumption of high-calorie foods caused compulsive overeating in rats. Sexually mature animals that experienced deprivation from their mother in early ontogenesis showed increased compulsive overeating of high-carbohydrate foods relative to the controls (p < 0.001). Moreover, the consumption of standard briquetted feed did not change. Intranasal administration of anthorex reduced the manifestations of compulsive overeating in rats after weaning under conditions of intermittent consumption of high-calorie food compared to the control group (p < 0.05). Consumption of standard food did not differ relative to the control group, before and after the administration of the orexin antagonist. CONCLUSIONS: The study reveals new methods of studying and synthesizing peptide drugs based on orexin and its antagonists for the correction of compulsive overeating caused by chronic stress in ontogenesis.

Keywords

compulsive overeating / maternal deprivation / antorex / orexin

References

[1] 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

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

[3] Lebedev AA, Pyurveev SS, Sekste EA, et al. Models of maternal neglect and social isolation in ontogenesis evince elements of gambling dependence in animals, increasing GHSR1A expression in cerebral structures. Journal of addiction problems. 2022;(11-12):44–66. EDN: SSLSSZ

[4] Лебедев А.А., Пюрвеев С.С., Сексте Э.А., и др. Модели материнского пренебрежения и социальной изоляции в онтогенезе проявляют у животных элементы игровой зависимости, повышая экспрессию GHSR1A в структурах мозга // Вопросы наркологии. 2022. № 11–12. С. 44–66. EDN: SSLSSZ

[5] Cottone P, Sabino V, Roberto M, et al. CRF system recruitment mediates dark side of compulsive eating. PNAS USA. 2009;106(47):20016–20020. doi: 10.1073/pnas.0908789106

[6] Cottone P., Sabino V., Roberto M., et al. CRF system recruitment mediates dark side of compulsive eating // PNAS USA. 2009. Vol. 106, N 47. P. 20016–20020. doi: 10.1073/pnas.0908789106

[7] Moore CF, Sabino V, Koob GF, Cottone P. Neuroscience of compulsive eating behavior. Front Neurosci. 2017;11:469. doi: 10.3389/fnins.2017.00469

[8] Moore C.F., Sabino V., Koob G.F., Cottone P. Neuroscience of compulsive eating behavior // Front Neurosci. 2017. Vol. 11. ID 469. doi: 10.3389/fnins.2017.00469

[9] Pyurveev SS, Sizov VV, Lebedev AA, et al. Registration of changes in the level of extracellular dopamine in the nucleus accumbens by fast-scan cyclic voltammetry during stimulation of the zone of the ventral tegmentаl area, which also caused a self-stimulation. J Evol Biochem Physiol. 2022;58(5):1613–1622. doi: 10.1134/s0022093022050295

[10] Pyurveev S.S., Sizov V.V., Lebedev A.A., et al. Registration of changes in the level of extracellular dopamine in the nucleus accumbens by fast-scan cyclic voltammetry during stimulation of the zone of the ventral tegmentаl area, which also caused a self-stimulation // J Evol Biochem Physiol. 2022. Vol. 58, N 5. P. 1613–1622. doi: 10.1134/s0022093022050295

[11] Pyurveev SS, Nekrasov MS, Dedanishvili NS, et al. Chronic mental stress in early ontogenesis increased risks of development for chemical and non-chemical forms of addiction. Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(1):69–78. EDN: GJBUYN doi: 10.17816/RCF21169-78

[12] Пюрвеев С.С., Некрасов М.С., Деданишвили Н.С., и др. Действие хронического психического стресса в раннем онтогенезе повышает риски развития химической и нехимической форм зависимости // Обзоры по клинической фармакологии и лекарственной терапии. 2023. Т. 21, № 1. С. 69–78. EDN: GJBUYN doi: 10.17816/RCF21169-78

[13] Moore CF, Panciera JI, Sabino V, Cottone P. Neuropharmacology of compulsive eating. Philos Trans R Soc Lond B Biol Sci. 2018;373(1742):24. doi: 10.1098/rstb.2017.0024

[14] Moore C.F., Panciera J.I., Sabino V., Cottone P. Neuropharmacology of compulsive eating // Philos Trans R Soc Lond B Biol Sci. 2018. Vol. 373, N 1742. ID 24. doi: 10.1098/rstb.2017.0024

[15] Geiger BM, Haburcak M, Avena NM, et al. Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity. Neurosci. 2009;159(4):1193–1199. doi: 10.1016/j.neuroscience.2009.02.007

[16] Geiger B.M., Haburcak M., Avena N.M., et al. Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity // Neurosci. 2009. Vol. 159, N 4. P.1193–1199. doi: 10.1016/j.neuroscience.2009.02.007

[17] Nathan P, Bullmore E. From taste hedonics to motivational drive: central μ-opioid receptors and binge-eating behavior. Int J Neuropsychopharmacol. 2009;12(7):995–1008. doi: 10.1017/s146114570900039x

[18] Nathan P., Bullmore E. From taste hedonics to motivational drive: central μ-opioid receptors and binge-eating behavior // Int J Neuropsychopharmacol. 2009. Vol. 12, N 7. P. 995–1008. doi: 10.1017/s146114570900039x

[19] Aston-Jones G, Smith RJ, Sartor H, et al. Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction. Brain Res. 2010;1314:74–90. doi: 10.1016/j.brainres.2009.09.106

[20] Aston-Jones G., Smith R.J., Sartor H., et al. Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction // Brain Res. 2010. Vol. 1314. P. 74–90. doi: 10.1016/j.brainres.2009.09.106

[21] Arendt DH, Hassell J, Li H, et al. Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. Psychoneuroendocrinol. 2014;40:17–26. doi: 10.1016/j.psyneuen.2013.10.010

[22] Arendt D.H., Hassell J., Li H., et al. Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala // Psychoneuroendocrinol. 2014. Vol. 40. P. 17–26. doi: 10.1016/j.psyneuen.2013.10.010

[23] Lebedev AA, Bessolova YN, Efimov NS, et al. Role of orexin peptide system in emotional overeating induced by brain reward stimulation in fed rats. Res Results Pharmacol. 2020;6(2):81–91. doi: 10.3897/ rrpharmacology.6.52180

[24] Lebedev A.A., Bessolova Y.N., Efimov N.S., et al. Role of orexin peptide system in emotional overeating induced by brain reward stimulation in fed rats // Res Results Pharmacol. 2020. Vol. 6, N 2. P. 81–91. doi: 10.3897/rrpharmacology.6.52180

[25] Lebedev AA, Pyurveev SS, Sexte EA, et al. Studying the involvement of ghrelin in the mechanism of gambling addiction in rats after exposure to psychogenic stressors in early ontogenesis. J Evol Biochem Physiol. 2023;59(4):1402–1413. doi: 10.1134/S1234567823040316

[26] Lebedev A.A., Pyurveev S.S., Sexte E.A., et al. Studying the involvement of ghrelin in the mechanism of gambling addiction in rats after exposure to psychogenic stressors in early ontogenesis // J Evol Biochem Physiol. 2023. Vol. 59, N 4. P. 1402–1413. doi: 10.1134/S1234567823040316

[27] Tata DA. Maternal separation as a model of early stress: Effects on aspects of emotional behavior and neuroendocrine function. Hell J Psychol. 2012;9(1):84–101.

[28] Tata D.A. Maternal separation as a model of early stress: Effects on aspects of emotional behavior and neuroendocrine function // Hell J Psychol. 2012. Vol. 9, N 1. P. 84–101.

[29] Naqavi MR, Mohammadi M, Salari V, Nakhaee N. The relationship between childhood maltreatment and opiate dependency in adolescence and middle age. Addict Health. 2011;3(3-4):92–98.

[30] Naqavi M.R., Mohammadi M., Salari V., Nakhaee N. The relationship between childhood maltreatment and opiate dependency in adolescence and middle age // Addict Health. 2011. Vol. 3, N 3-4. P. 92–98.

[31] Moffett MC, Vicentic A, Kozel M, et al. Maternal separation alters drug intake patterns in adulthood in rats. Biochem Pharmacol. 2007;73(3):321–330. doi: 10.1016/j.bcp.2006.08.003

[32] Moffett M.C., Vicentic A., Kozel M., et al. Maternal separation alters drug intake patterns in adulthood in rats // Biochem Pharmacol. 2007. Vol. 73, N 3. P. 321–330. doi: 10.1016/j.bcp.2006.08.003

[33] Lebedev AA, Lukashkova VV, Pshenichnaya AG, et al. A new ghrelin receptor antagonist agrelax participates in the control of emotional-explorative behavior and anxiety in rats. Psychopharmacology and biological narcology. 2023;14(1):69–79. EDN: LPJPUM doi: 10.17816/phbn321624

[34] Лебедев А.А., Лукашкова В.В., Пшеничная А.Г., и др. Новый антагонист рецепторов грелина агрелакс участвует в контроле эмоционально-исследовательского поведения и уровня тревожности у крыс // Психофармакология и биологическая наркология. 2023. Т. 14, № 1. С. 69–79. EDN: LPJPUM doi: 10.17816/phbn321624

[35] Rossi MA, Stuber GD. Overlapping brain circuits for homeostatic and hedonic feeding. Cell Metab. 2018;27(1):42–56. doi: 10.1016/j.cmet.2017.09.021

[36] Rossi M.A., Stuber G.D. Overlapping brain circuits for homeostatic and hedonic feeding // Cell Metab. 2018. Vol. 27, N 1. P. 42–56. doi: 10.1016/j.cmet.2017.09.021

[37] Cifani C, Polidori C, Melotto S, et al. A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate, and midazolam. Psychopharmacol (Berl). 2009;204(1):113–125. doi: 10.1007/s00213-008-1442-y

[38] Cifani C., Polidori C., Melotto S., et al. A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate, and midazolam // Psychopharmacol (Berl). 2009. Vol. 204, N 1. P. 113–125. doi: 10.1007/s00213-008-1442-y

[39] Kim HJJ, Zagzoog A, Ceni C, et al. Dual cannabinoid and orexin regulation of anhedonic behaviour caused by prolonged restraint stress. Brain Sci. 2023;13(2):314. doi: 10.3390/brainsci13020314

[40] Kim H.J.J., Zagzoog A., Ceni C., et al. Dual cannabinoid and orexin regulation of anhedonic behaviour caused by prolonged restraint stress // Brain Sci. 2023. Vol. 13, N 2. ID 314. doi: 10.3390/brainsci13020314

[41] 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. Neuropsychopharmacol. 2012;37(9):1999–2011. doi: 10.1038/npp.2012.48

[42] 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 // Neuropsychopharmacol. 2012. Vol. 37, N 9. P. 1999–2011. doi: 10.1038/npp.2012.48

[43] Valdivia S, Cornejo MP, Reynaldo M, et al. Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling. Psychoneuroendocrinol. 2015;60:206–216. doi: 10.1016/j.psyneuen.2015.06.018

[44] Valdivia S., Cornejo M.P., Reynaldo M., et al. Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling // Psychoneuroendocrinol. 2015. Vol. 60. P. 206–216. doi: 10.1016/j.psyneuen.2015.06.018

[45] Schuller J, Koch M. Investigating a role of orexin and ‘cocaine- and amphetamine-regulated transcript’ in the nucleus accumbens shell in binge eating of male rats and the relationship with impulsivity. Physiol Behav. 2022;257:114000. doi: 10.1016/j.physbeh.2022.114000

[46] Schuller J., Koch M. Investigating a role of orexin and ‘cocaine- and amphetamine-regulated transcript’ in the nucleus accumbens shell in binge eating of male rats and the relationship with impulsivity // Physiol Behav. 2022. Vol. 257. ID 114000. doi: 10.1016/j.physbeh.2022.114000

[47] Shabanov PD, Ganapolsky VP, Elistratov AA. Comparative study of meteoadaptogenic properties of peptide and nonpeptide drugs in volunteers. Medical academic journal. 2007;7(2):42–48. EDN: IAKGDR

[48] Шабанов П.Д., Ганапольский В.П., Елистратов А.А. Сравнительное изучение метеоадаптогенных свойств пептидных и непептидных препаратов у добровольцев // Медицинский академический журнал. 2007. Т. 7, № 2. С. 42–48. EDN: IAKGDR

[49] Karpova IV, Bychkov ER, Lebedev AA, Shabanov PD. Monoaminergic effects of the unilateral blockade of orexin receptors (OX1R) in the enlarged amygdala under psychostimulant action. Psychopharmacology and biological narcology. 2023;14(1):48–62. EDN: VIUURH doi: 10.17816/phbn321621

[50] Карпова И.В., Бычков Е.Р., Лебедев А.А., Шабанов П.Д. Моноаминергические эффекты унилатеральной блокады орексиновых рецепторов (OX1R) в структурах расширенной миндалины на фоне системного действия психостимулятора // Психофармакология и биологическая наркология. 2023. Т. 14, № 1. С. 48–62. EDN: VIUURH doi: 10.17816/phbn321621

RIGHTS & PERMISSIONS

Eco-Vector