Skip to main content
SpringerLink
Log in

Studying the Involvement of Ghrelin in the Mechanism of Gambling Addiction in Rats after Exposure to Psychogenic Stressors in Early Ontogenesis

  • Experimental Papers
  • Published:
Journal of Evolutionary Biochemistry and Physiology Aims and scope Submit manuscript

Abstract

We investigated the role of ghrelin and its receptors in the manifestation of gambling addiction elements in rats exposed to early psychogenic stress. Rearing in conditions of social isolation or maternal deprivation in early ontogeny increased risk behavior and impulsivity in the Iowa Gambling Task test: animals sought more food reinforcement, but with a low probability. Maternal deprivation or rearing in social isolation increased expression of Ghsr in the amygdala and hypothalamus respectively. The level of expression of the gene under study in the prefrontal cortex did not change. It is concluded that early psychogenic stress causes an imbalance in the brain ghrelin regulatory system, which manifests itself in increased of Ghsr level as well as elements of gambling addiction. The scheme of the effect of chronic stress on the hypothalamic ghrelin system and on the extrahypothalamic regulation of ghrelin is presented.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

REFERENCES

  1. Fenoglio KA, Brunson KL, Baram TZ (2006) Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects. Front Neuroendocrinol 27(2): 180–192. https://doi.org/10.1016/j.yfrne.2006.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Catani C, Jacob N, Schauer E, Kohila M, Neuner F (2008) Family violence, war, and natural disasters: a study of the effect of extreme stress on children’s mental health in Sri Lanka. BMC Psychiatry 8: 33. https://doi.org/10.1186/1471-244X-8-33

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lang AJ, Aarons GA, Gearity J, Laffaye C, Satz L, Dresselhaus TR, Stein MB (2008) Direct and indirect links between childhood maltreatment, posttraumatic stress disorder, and women’s health. Behav Med 33(4): 125–135. https://doi.org/10.3200/BMED.33.4.125-136

    Article  PubMed  Google Scholar 

  4. Tata D (2012) Maternal separation as a model of early stress: Effects on aspects of emotional behavior and neuroendocrine function. Hellenic J Psychol 9: 84–101.

    Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  6. Nishi M, Horii-Hayashi N, Sasagawa T, Matsunaga W (2013) Effects of early life stress on brain activity: implications from maternal separation model in rodents. Gen Comp Endocrinol 181: 306–309.

    Article  CAS  PubMed  Google Scholar 

  7. Moffett MC, Vicentic A, Kozel M, Plotsky P, Francis DD, Kuhar MJ (2007) Maternal separation alters drug intake patterns in adulthood in rats. Biochem Pharmacol 73(3): 321–330.

    Article  CAS  PubMed  Google Scholar 

  8. Krupina NA, ShISenova SD, Khlebnikova NN (2020) Prolonged social isolation, started early in life, impairs cognitive abilities in rats depending on sex. Brain Sci 10(11): 1–29.

    Article  Google Scholar 

  9. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762): 656–660. https://doi.org/10.1038/45230

    Article  CAS  PubMed  Google Scholar 

  10. Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A (2009) Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev 61(4): 430–481. https://doi.org/10.1124/pr.109.001958

    Article  CAS  PubMed  Google Scholar 

  11. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M (2002) The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metabol 87(6): 2988. https://doi.org/10.1210/jcem.87.6.8739

    Article  CAS  Google Scholar 

  12. Perello M, Sakata I, Birnbaum S, Chuang JC, Osborne-Lawrence S, Rovinsky SA, Woloszyn J, Yanagisawa M, Lutter M, Zigman JM (2010) Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol Psychiatr 67(9): 880–886. https://doi.org/10.1016/j.biopsych.2009.10.030

    Article  CAS  Google Scholar 

  13. Carroll ME, France CP, Meisch RA (1979) Food deprivation increases oral and intravenous drug intake in rats. Science (New York) 205(4403): 319–321. https://doi.org/10.1126/science.36665

  14. Kharbanda KK, Farokhnia M, Deschaine SL, Bhargava R, Rodriguez-Flores M, Casey C A, Goldstone AP, Jerlhag E, Leggio L, Rasineni K (2022) Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review. Alcoholism, Clin and Exp Res 46(12): 2149–2159. https://doi.org/10.1111/acer.14967

    Article  CAS  Google Scholar 

  15. Jerlhag E, Egecioglu E, Dickson SL, Engel JA (2011) Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system. Addiction Biol 16(1): 82–91. https://doi.org/10.1111/j.1369-1600.2010.00231.x

    Article  CAS  Google Scholar 

  16. Ducharme R, Anisman H, Abizaid A (2010) Altered metabolic and neurochemical responses tochronic unpredictable stressors in ghrelin receptor-deficient mice. Eur J Neurosci 32(4): 632–639. https://doi.org/10.1111/j.1460-9568.2010.07310

    Article  PubMed  Google Scholar 

  17. Shabanov PD, Yakushina ND, Lebedev AA (2020) Pharmacology of peptide mechanisms of gambling behavior in rats. Vopr Narkol 4(187): 24–44. (In Russ).

    Google Scholar 

  18. Geisel O, Panneck P, Hellweg R, Wiedemann K, Muller CA (2015) Hypothalamic-pituitary-adrenal axis activity in patients with pathological gambling and internet use disorder. Psychiatry Res 226: 97–102. https://doi.org/10.1016/j.psychres.2014.11.078

    Article  CAS  PubMed  Google Scholar 

  19. Lebedev AA, Karpova IV, Bychkov ER, Yakushina ND, Thyssen IY, Gramota KE, Efimov NS, Shabanov PD (2022) 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 52(3): 415–421. https://doi.org/10.1007/s11055-022-01255-x

    Article  CAS  Google Scholar 

  20. Sekste EA, Lebedev AA, Bychkov ER, Airapetov MI, Gramota KE, Tissen IY, Shabanov PD (2021) Increase in the level of orexin receptor 1 (OX1R) mRNA in the brain structures of rats prone to impulsivity in behavior. Biomed Chem 67(5): 411–417. (In Russ).

    CAS  Google Scholar 

  21. Lebedev AA, Khokhlov PP, Yakushina ND, Gramota KE, Tissen IYu, Bychkov ER, Airapetov MI, Shabanov PD (2021) Pharmacological and biochemical analysis of participation of the ghrelin peptide system in behavioral manifestations of gambling in rats. Eksper klin farmakol 82(6): 16–20. (In Russ).

    Google Scholar 

  22. Balakina ME, Degtyareva EV, Nekrasov MS, Brus TV, Purveev SS (2021) Effect of early postnatal stress upon psychoemotional state and development of excessive consumption of high-carbohydrate food in rats. Russ Biomed Res 6(2): 27–37. (In Russ).

    Google Scholar 

  23. Wang S, Wang J, Lv X (2018) Selection of reference genes for expression analysis in mouse models of acute alcoholic liver injury. Int J Mol Med 41(6): 3527–3536. https://doi.org/10.3892/ijmm.2018.3527

    Article  CAS  PubMed  Google Scholar 

  24. Yang B, Cai G, Xiong C, Huang J (2021) Relative Deprivation and Game Addiction in Left-Behind Children: A Moderated Mediation. Front Psychol 12: 639051. https://doi.org/10.3389/fpsyg.2021.639051

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sekste EA, Lebedev AA, Bychkov ER, Airapetov MI, Gramota KE, Thyssen IY, Shabanov PD (2021) Increase in the level of orexin receptor 1 (OX1R) mRNA in the brain structures of rats prone to impulsivity in behavior. Biomed Chem 67(5): 411–417. https://doi.org/10.18097/PBMC20216705411

    Article  CAS  Google Scholar 

  26. Alvarez-Crespo M, Skibicka KP, Farkas I, Molnár CS, Egecioglu E, Hrabovszky E, Liposits Z, Dickson SL (2012) The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence. PloS One 7(10): e46321. https://doi.org/10.1371/journal.pone.0046321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vetlugin EA, Bychkov ER, Abrosimov ME, Moskalyev AR, Pshenichnaya AG, Pyurveev SS, Lebedev VA, Lebedev AA, Shabanov PD (2022) Anxiolytic and antidepressant effects of melanin-concentrating hormone 1 receptor antagonist SNAP 94847. Pediatriya 82(6): 16–20. (In Russ).

    Google Scholar 

  28. Andrews ZB (2011) The extra-hypothalamic actions of ghrelin on neuronal function. Trends Neurosci 34(1): 31–40. https://doi.org/10.1016/j.tins.2010.10.001

    Article  CAS  PubMed  Google Scholar 

  29. Airapetov MI, Eresko SO, Lebedev AA, Bychkov ER, Shabanov PD (2021) Expression of the growth hormone secretagogue receptor 1a (GHS-R1a) in the brain. Physiol Rep 9(21): e15113. https://doi.org/10.14814/phy2.15113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Leggio L, Zywiak WH, Fricchione SR, Edwards SM, de la Monte SM, Swift RM, Kenna GA (2014) Intravenous ghrelin administration increases alcohol craving in alcohol-dependent heavy drinkers: a preliminary investigation. Biol Psychiatry 76(9): 734–741. https://doi.org/10.1016/j.biopsych.2014.03.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hemmann K, Raekallio M, Kanerva K, Hänninen L, Pastell M, Palviainen M, Vainio O (2012) Circadian variation in ghrelin and certain stress hormones in crib-biting horses. Veterin J 193(1): 97–102. https://doi.org/10.1016/j.tvjl.2011.09.027

    Article  CAS  Google Scholar 

  32. Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM (2008) The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nature Neurosci 11(7): 752–753. https://doi.org/10.1038/nn.2139

    Article  CAS  PubMed  Google Scholar 

  33. Cabral A, Suescun O, Zigman JM, Perello M (2012) Ghrelin indirectly activates hypophysiotropic CRF neurons in rodents. PloS One 7(2): e31462. https://doi.org/10.1371/journal.pone.0031462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cabral A, Portiansky E, Sánchez-Jaramillo E, Zigman JM, Perello M (2016) Ghrelin activates hypophysiotropic corticotropin-releasing factor neurons independently of the arcuate nucleus. Psychoneuroendocrinology 67: 27–39. https://doi.org/10.1016/j.psyneuen.2016.01.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Roik RO, Lebedev AA, Shabanov PD (2019) The value of extended amygdala structures in emotive effects of narcogenic with diverse chemical structure. Res Pharmacol 5(3): 11–19. https://doi.org/10.3897/npharmacology.5.38389

    Article  CAS  Google Scholar 

  36. Koob GF (2009) Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology 56(1): 18–31. https://doi.org/10.1016/j.neuropharm.2008.07.043

    Article  CAS  PubMed  Google Scholar 

  37. Klein AK, Brito MA, Akhavan S, Flanagan DR, Le N, Ohana T, Patil AS, Purvis EM, Provenzano C, Wei A, Zhou L, Ettenberg A (2017) Attenuation of the anxiogenic effects of cocaine by 5-HT1B autoreceptor stimulation in the bed nucleus of the stria terminalis of rats. Psychopharmacology 234(3): 485–495. https://doi.org/10.1007/s00213-016-4479-3

    Article  CAS  PubMed  Google Scholar 

  38. Pina MM, Cunningham CL (2017) Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit. Neurobiol Learning and Memory 137: 83–91. https://doi.org/10.1016/j.nlm.2016.11.013

    Article  CAS  Google Scholar 

  39. Aguilera G, Liu Y (2012) The molecular physiology of CRH neurons. Front Neuroendocrinol 33(1): 67–84. https://doi.org/10.1016/j.yfrne.2011.08.002

    Article  CAS  PubMed  Google Scholar 

  40. Cabral A, Suescun O, Zigman JM, Perello M (2012) Ghrelin indirectly activates hypophysiotropic CRF neurons in rodents. PLoS One 7(2): e31462. https://doi.org/10.1371/journal.pone.0031462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Willesen MG, Kristensen P, Rømer J (1999) Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70(5): 306–316. https://doi.org/10.1159/000054491

    Article  CAS  PubMed  Google Scholar 

  42. Marais L, van Rensburg SJ, van Zyl JM, Stein DJ, Daniels WM (2008). Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res 61(1): 106–112. https://doi.org/10.1016/j.neures.2008.01.011

    Article  CAS  PubMed  Google Scholar 

  43. Zoicas I, Neumann ID (2016) Material separation facilitates extinction of social fear in adult male mice. Behav Brain Res 297: 323–328. https://doi.org/10.1016/j.bbr.2015.10.034

    Article  PubMed  Google Scholar 

  44. Plotsky PM, Thrivikraman KV, Nemeroff CB, Caldji C, Sharma S, Meaney MJ (2005) Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. Neuropsychopharmacology 30(12): 2192–2204. https://doi.org/10.1038/sj.npp.1300769

    Article  CAS  PubMed  Google Scholar 

  45. Salzmann C, Otis M, Long H, Roberge C, Gallo-Payet N, Walker CD (2004) Inhibition of steroidogenic response to adrenocorticotropin by leptin: implications for the adrenal response to maternal separation in neonatal rats. Endocrinology 145(4): 1810–1822. https://doi.org/10.1210/en.2003-1514

    Article  CAS  PubMed  Google Scholar 

  46. Schmidt MV, Levine S, Alam S, Harbich D, Sterlemann V, Ganea K, de Kloet ER, Holsboer F, Müller MB (2006). Metabolic signals modulate hypothalamic-pituitary-adrenal axis activation during maternal separation of the neonatal mouse. J Neuroendocrinol 18(11): 865–874. https://doi.org/10.1111/j.1365-2826.2006.01482.x

    Article  CAS  PubMed  Google Scholar 

  47. Shabanov PD, Lebedev AA, Mescherov ShK (2002) Dopamine and thereinforcing systems of the brain. Saint Petersburg. (In Russ).

    Google Scholar 

  48. Lebedev AA, Moskalev AR, Abrosimov ME, Vetlugin EA, Pshenichnaya AG, Lebedev VA, Evdokimova NR, Bychkov ER, Shabanov PD (2021) Effect of neuropeptide antagonist BMS193885 on overeating and emotional responses induced by social isolation in rats. Rev Clin Pharmacol and Drug Therapy 19(2): 189–202. (In Russ).

    Article  Google Scholar 

  49. Reichardt BA, Shabanov PD (2022) Ghrelin mechanisms of nutritional reward. Part 2. Interaction of ghrelin with hormones, neuropeptides and other endogenous ligands. Rev Clin Pharmacol and Drug Therapy 20(3): 229–254. https://doi.org/10.17816/RCF203229-254

    Article  Google Scholar 

Download references

Funding

The work was performed within the framework of the state task of the Ministry of Education and Science of Russia (2022–2025). “Search for molecular targets for pharmacological action in addictive and neuroendocrine disorders and creation of new pharmacologically active substances acting on CNS receptors,” code FGWG-2022-0004.

Author information

Authors and Affiliations

  1. Institute of Experimental Medicine, St. Petersburg, Russia

    A. A. Lebedev, S. S. Purveev, E. A. Sexte, B. A. Reichardt, E. R. Bychkov & P. D. Shabanov

  2. St. Petersburg State Pediatric Medical University, St. Petersburg, Russia

    S. S. Purveev

Authors
  1. A. A. Lebedev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. S. Purveev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. A. Sexte
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. A. Reichardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. R. Bychkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. D. Shabanov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.A.L.—idea of work, planning the experiment, discussion, writing and editing the article. S.S.P.—collecting data in the experiment, data processing, writing and editing the article. E.A.S.—collecting data in the experiment, processing the data, performing PCR analysis. B.A.R.—creating a scheme of stress action, discussing the data obtained. E.R.B.- statistical processing of data, writing and editing the article. P.D.Sh.—general management, discussion, writing and editing of the article.

Corresponding author

Correspondence to A. A. Lebedev.

Ethics declarations

COMPLIANCE WITH ETHICAL STANDARDS

The experiments were conducted in accordance with the ethical principles outlined in Directive 2010/63/EC of the European Parliament and the Council of the European Union of September 22, 2010, and approved by the Bioethics Commission of FGBNU “Institute of Experimental Medicine.”

CONFLICT OF INTEREST

The authors declare that they have no conflicts of interest.

Additional information

Translated by A. Dyomina

Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 8, pp. 1080–1093https://doi.org/10.31857/S086981392308006X.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lebedev, A.A., Purveev, 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 Phys 59, 1402–1413 (2023). https://doi.org/10.1134/S1234567823040316

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1234567823040316

Keywords:

Search

Navigation