Антиаддиктивный потенциал двойного агониста инкретиновых рецепторов тирзепатида в тесте на эмоциональное переедание, вызванное внутримозговой самостимуляцией: ОРИГИНАЛЬНЫЕ СТАТЬИ

Николай Сергоевич  Деданишвили; Сарнг Саналович  Пюрвеев; Андрей Андреевич  Лебедев; Андрей Глебович  Васильев; Петр Дмитриевич  Шабанов; Дмитрий Анатольевич  Лебедев

doi:10.56871/PED.2025.78.21.005

Anti-addictive potential of the dual incretin receptor agonist tirzepatide in a model of emotional overeating induced by intracranial self-stimulation

ORIGINAL STUDIES

Nikolay S. Dedanishvili Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia
Sarng S. Pyurveev Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia
Andrey A. Lebedev Institute of Experimental Medicine, Saint Petersburg, Russia
Andrey G. Vasiliev Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia
Petr D. Shabanov Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia
Dmitry A. Lebedev Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia

Keywords:

инкретины тирзепатид самостимуляция мозга система вознаграждения импульсивное поведение аддиктивное поведение incretins tirzepatide brain self-stimulation reward system impulsive behavior addictive behavior

Abstract

Background. The incretin system (GLP-1 and GIP) plays a key role in the regulation of energy metabolism and feeding behavior. Recent research has demonstrated that incretin receptor agonists can modulate not only metabolic processes but also neuronal mechanisms of reward, highlighting their potential use in managing impulsive and addictive disorders.

Aim — to assess the effect of the dual incretin receptor agonist tirzepatide on operant and feeding behavior in rats in the intracranial self-stimulation (ICSS) test.

Material and methods. The experiment involved 24 male Wistar rats. Tirzepatide was administered subcutaneously (s.c.) at doses of 0.05, 0.10, and 0.30 mg/kg once daily for 7 days. Behavioral testing was performed 1 hour after injection, including the ICSS test (number of lever presses per minute) and the feeding test (number of seeds eaten per minute). Statistical analysis was performed using the Kruskal–Wallis test followed by Dunn’s post hoc test (p <0.05).

Results. A single administration of tirzepatide produced no significant differences compared with control (H=3.5; p=0.38). On day 3, a significant reduction in lever-pressing was observed at 0.30 mg/kg (approximately 15–20% below control; H=13.69; p <0.001; Dunn p <0.01) along with a decrease in food intake (H=9.64; p <0.05; Dunn p <0.05). By day 7, a stable dose-dependent suppression of both operant and feeding behavior was recorded (ICSS: H=13.13; p <0.01; feeding: H=14.16; p <0.01) with significant differences at 0.10 and 0.30 mg/kg.

Conclusion. Repeated administration of tirzepatide, a dual incretin receptor agonist, produces a pronounced dose- and time-dependent reduction in motivational and feeding activity in rats.

References

Müller T.D., Finan B., Bloom S.R. et al. Glucagon-like peptide 1 (GLP-1). Molecular Metabolism. 2019;30:72–130. https://doi.org/10.1016/j.molmet.2019.09.010.

Holst J.J. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–1439. https://doi.org/10.1152/physrev.00034.2006.

Alhadeff A.L., Rupprecht L.E., Hayes M.R. GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control food intake. Endocrinol. 2012;153(2):647–658. https://doi.org/10.1210/en.2011-1443.

Graham D.L., Durai H.H., Trammell T.S. et al. A novel mouse model of glucagon-like peptide-1 receptor expression: A look at the brain. J Comp Neurol. 2020;528(14):2445–2470. https://doi.org/10.1002/cne.24905.

Мамонтова Е.Д., Мичурина С.С., Стафеев Ю.С. и др. Прямое действие синтетического аналога глюкагоноподобного пептида 1-го типа, лираглутида, на зрелые адипоциты реализуется через аденилатциклаза-зависимое усиление инсулиновой чувствительности. Биохимия. 2021;86(3):409–421. https://doi.org/10.31857/S032097252103009X.

Хайкина Е.В., Козлов С.Н., Залеская А.И. и др. Современные аспекты инкретиновой фармакотерапии: путь от физиологических эффектов инкретинов к лечению сахарного диабета 2 типа и ожирения. Клиническая фармакология и терапия. 2025;34(3):40–46. https://doi.org/10.32756/0869-5490-2025-3-40-46.

Vallof D., Kalafateli A.L., Jerlhag E. Brain region specific glucagon-like peptide-1 receptors regulate alcohol-induced behaviors in rodents. Psychoneuroendocrinology. 2019;103:284–295. https://doi.org/10.1016/j.psyneuen.2019.02.006.

Thomsen M., Holst J.J., Molander A. et al. Effects of glucagon-like peptide 1 analogs on alcohol intake in alcohol-preferring vervet monkeys. Psychopharmacology (Berlin). 2019;236(2):603–611. https://doi.org/10.1007/s00213-018-5089-z.

Vallof D., Kalafateli A.L., Jerlhag E. Long-term treatment with a glucagon-like peptide-1 receptor agonist reduces ethanol intake in male and female rats. Trans Psychiatry. 2020;10(1):238. https://doi.org/10.1038/s41398-020-00923-1.

Шаршова О.Г., Чубаров Т.В., Гребенникова И.В. и др. Эффекты инкретинов и современные направления инкретинотропной терапии: обзор литературы. Научно-медицинский вестник Центрального Черноземья. 2024;25(4):21–26. https://doi.org/10.18499/1990-472X-2024-25-4-21-26.

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. Research Results in Pharmacology. 2020;6(1):81–91. https://doi.org/10.3897/rrpharmacology.6.52180.

Пестерева Н.С., Трактиров Д.С., Лебедев А.А., Пюрвеев С.С., Черкассова Р.Д., Шабанов П.Д. Регистрация высвобождения внеклеточного дофамина при самостимуляции методом циклической вольтамперометрии с быстрым сканированием. Обзоры по клинической фармакологии и лекарственной терапии. 2025;23(1):79–90. https://doi.org/10.17816/RCF651161.

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;59(4):1402–1413. https://doi.org/10.1134/s1234567823040316.

Sizov V.V., Lebedev A.A., Pyurveev S.S. et al. A method for training rats to electrical self-stimulation in response to raising the head using a telemetry apparatus to record extracellular dopamine levels. Neurosci Behav Physiol. 2024;54(1):52–60. https://doi.org/10.1007/s11055-024-01568-z.

Fink-Jensen A., Wörtwein G., Klausen M.K. et al. Effect of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide on alcohol consumption in alcohol-preferring male vervet monkeys. Psychopharmacol. 2025;242(1):63–70. https://doi.org/10.1007/s00213-024-06637-2.

Quddos F., Hubshman Z., Tegge A. et al. Semaglutide and Tirzepatide reduce alcohol consumption in individuals with obesity. Sci Rep. 2023;13(1);20998. https://doi.org/10.1038/s41598-023-48267-2.

Бычков Е.Р., Карпова И.В., Крюков А.С. и др. Обмен моноаминов в прилежащем ядре и стриатуме при активации положительных и отрицательных эмоциогенных зон латерального гипоталамуса у крыс. Наркология. 2020;19(5):38–43. https://doi.org/10.25557/1682-8313.2020.05.38-43.

Бычков Е.Р., Лебедев А.А., Ефимов Н.С., Крюков А.С., Карпова И.В., Пюрвеев С.С., Дробленков А.В., Шабанов П.Д. Особенности вовлечения дофаминергической и серотонинергической систем мозга в положительные и отрицательные эмоциональные состояния у крыс. Обзоры по клинической фармакологии и лекарственной терапии. 2020;18(2):123–130. https://doi.org/10.17816/RCF182123-130.

Merkel R., Hernandez N.S., Weir V. et al. An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking. Sci Adv. 2025;11(9):eadr5051. https://doi.org/10.1126/sciadv.adr5051.

Klausen M.K., Thomsen M., Wortwein G. et al. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. Br J Pharmacol. 2022;179(4):625–641. https://doi.org/10.1111/bph.15677.

Rosenberg J., Jacob J., Desai P. et al. Incretin hormones: pathophysiological risk factors and potential targets for type 2 diabetes. J Obes Metab Syndr. 2021;30(3):233–247. https://doi.org/10.7570/jomes21053.

Heise T., DeVries J.H., Urva S. et al. Tirzepatide reduces appetite, energy intake, and fat mass in people with type 2 diabetes. Diabetes Care. 2023;46(5);998–1004. https://doi.org/10.2337/dc22-1710.

Kooij K.L., Koster D.I., Eeltink E. et al. GLP-1 receptor agonist semaglutide reduces appetite while increasing dopamine reward signaling. Neuroscience Applied. 2023;3:103925. https://doi.org/10.1016/j.nsa.2023.103925.

Власов Т.Д., Симаненкова А.В., Дора С.В. и др. Механизмы нейропротективного действия инкретиномиметиков. Сахарный диабет. 2016;19(1):16–23. https://doi.org/10.14341/DM7192.

Douton J.E., Augusto C., Stoltzfus B. et al. Glucagon-like peptide-1 receptor agonist exendin-4 reduces reinstatement of heroin-seeking behavior in rats. Behav Pharmacol. 2021;32(4):265–277. https://doi.org/10.1097/fbp.0000000000000609.

Evans B., Stoltzfus B., Acharya N. et al. Dose titration with the glucagon-like peptide-1 agonist liraglutide reduces cue- and drug-induced heroin seeking in high drug-taking rats. Brain Res Bull. 2022;189:163–173. https://doi.org/10.1016/j.brainresbull.2022.08.022.