Dose- and time-dependent effects of the dual GIP/GLP-1 receptor agonist tirzepatide on emotional overeating in a rat model of intracranial self-stimulation

Background. Despite the increasing prevalence of emotional overeating and obesity, the specific neurohormonal mechanisms involved in the pathogenesis of these pathological processes remain poorly understood. The incretin system may serve as an important therapeutic target for the correction of these eating disorders.

Aim. To study the effects of the dual GIP/GLP-1 receptor agonist tirzepatide on feeding behavior parameters in a rat model of emotional overeating induced by intracranial self-stimulation (ICSS).

Methods. Experiments were performed on male Wistar rats with electrodes implanted in the ventral tegmental area. Tirzepatide was administered subcutaneously at doses of 0.05, 0.10, and 0.30 mg/kg for 7 days. Food intake (number of seeds consumed) was assessed at 1 minute, 30 minutes, and on days 3 and 7 after administration.

Results. No statistically significant changes in feeding activity were observed 30 minutes after tirzepatide administration. On the third day, a decrease in food intake was observed only at the maximum dose (0.30 mg/kg). On the seventh day, a significant anorexigenic effect was observed at doses of 0.10 and 0.30 mg/kg, indicating a doseand time-dependent effect.

Conclusion. Tirzepatide does not exert a significant acute effect on feeding activity in the emotional overeating model at 30 minutes after administration. Repeated administration of the drug revealed a doseand time-dependent anorexigenic effect, manifested by a decrease in food intake on days 3 and 7 of the experiment. The most pronounced decrease in feeding activity was observed at doses of 0.10 and 0.30 mg/kg on day 7.

1. Lillich FF, Imig JD, Proschak E. Multi-Target Approaches in Metabolic Syndrome. Front Pharmacol. 2021; 11: 554961. doi: 10.3389/fphar.2020.554961

2. Artasensi A, Pedretti A, Vistoli G, Fumagalli L. Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs. Molecules. 2020; 25(8): 1987. doi: 10.3390/molecules25081987

3. Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020; 5(17): e140532. doi: 10.1172/jci.insight.140532

4. Arillotta D, Floresta G, Papanti Pelletier GD, Guirguis A, Corkery JM, Martinotti G, et al. Exploring the potential impact of GLP-1 receptor agonists on substance use, compulsive behavior, and libido: insights from social media using a mixed-methods approach. Brain Sci. 2024; 14(6): 617. doi: 10.3390/brainsci14060617

5. Brunchmann A, Thomsen M, Fink-Jensen A. The effect of glucagon-like peptide-1 (GLP-1) receptor agonists on substance use disorder (SUD)-related behavioural effects of drugs and alcohol: a systematic review. Physiol Behav. 2019; 206: 232–42. doi: 10.1016/j.physbeh.2019.03.029

6. Razzaki TS, Weiner A, Shukla AP. Tirzepatide: does the evidence to date show potential for the treatment of early stage type 2 diabetes? Ther Clin Risk Manag. 2022; 18: 955–64. doi: 10.2147/TCRM.S328056

7. Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, Milicevic Z, Haupt A, Robins DA. Dual GIP and GLP1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. J Clin Endocrinol Metab. 2021; 106(2): 388-396. doi: 10.1210/clinem/dgaa863

8. Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Metab. 2020; 31(6): 410–21. doi: 10.1016/j.tem.2020.02.006

9. Sizov VV, Lebedev AA, Pyurveev SS, 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. doi: 10.1007/s11055-024-01568-z

10. 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(1): 81–91. doi: 10.3897/rrpharmacology.6.52180

11. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022; 387(3): 205–216. doi: 10.1056/NEJMoa2206038

12. Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021; 398(10295): 143–155. doi: 10.1016/S0140-6736(21)01324-6

13. Secher A, Jelsing J, Baquero AF, Hecksher-Sørensen J, Cowley MA, Dalbøge LS, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014; 124(10): 4473–4488. doi: 10.1172/JCI75276

14. Alhadeff AL, Rupprecht LE, Hayes MR. GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control food intake. Endocrinology. 2012; 153(2): 647–658. doi: 10.1210/en.2011-1443

15. Bae JH, Choi HJ, Cho KIK, Kim LK, Kwon JS, Cho YM. Glucagon-like peptide-1 receptor agonist differentially affects brain activation in response to visual food cues in lean and obese individuals with type 2 diabetes mellitus. Diabetes Metab J. 2020; 44(2): 248–259. doi: 10.4093/dmj.2019.0018

16. Choi W, Nho YH, Qiu L, Chang A, Campos G, Seilheimer RL, et al. Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide. Nat Med. 2025; 31(12): 4038–4043. doi: 10.1038/s41591-025-04035-5

17. van Ruiten CC, Ten Kulve JS, van Bloemendaal L, Nieuwdorp M, Veltman DJ, IJzerman RG. Eating behavior modulates the sensitivity to the central effects of GLP-1 receptor agonist treatment: a secondary analysis of a randomized trial. Psychoneuroendocrinology. 2022; 137: 105667. doi: 10.1016/j.psyneuen.2022.105667

18. Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Metab. 2020; 31(6): 410–421. doi: 10.1016/j.tem.2020.02.006

19. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021; 385(6): 503–515. doi: 10.1056/NEJMoa2107519

20. Martin CK, Carmichael OT, Carnell S, Considine RV, Kareken DA, Dydak U, et al. Tirzepatide on ingestive behavior in adults with overweight or obesity: a randomized 6-week phase 1 trial. Nat Med. 2025; 31(9): 3141–50. doi: 10.1038/s41591-025-03774-9

21. Fortin SM, Roitman MF. Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core. Physiol Behav. 2017; 176: 17–25. doi: 10.1016/j.physbeh.2017.03.019

22. Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015; 21(1): 27–36. doi: 10.1038/nm.3761

23. Galindo RJ, Cheng AYY, Longuet C, Ai M, Coskun T, Malik R, et al. Insights into the mechanism of action of tirzepatide: a narrative review. Diabetes Ther. 2026; 17(1): 19–40. doi: 10.1007/s13300-025-01804-w

24. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022; 387(3): 205–216. doi: 10.1056/NEJMoa2206038

25. Fisman EZ, Tenenbaum A. The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovasc Diabetol. 2021; 20(1): 225. doi: 10.1186/s12933-021-01412-5

26. Chavda VP, Ajabiya J, Teli D, Bojarska J, Apostolopoulos V. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: a mini-review. Molecules. 2022; 27(13): 4315. doi: 10.3390/molecules27134315