Prospects for research into the neurochemistry and pharmacology of gaming disorder

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Abstract

Currently, there are neither generally accepted approaches to the therapy of gaming disorder nor any medication officially approved for this indication. Available treatment strategies include psychotherapeutic interventions and pharmacotherapy using antidepressants, opioid receptor antagonists, mood stabilizers, N-methyl-D-aspartate receptor antagonists, and antipsychotics. This review analyzes the prospects for investigating the neurochemistry and pharmacology of gaming disorder. The dopaminergic and serotonergic systems make the greatest contribution to the functional state underlying gambling behavior. Of particular interest are the effects of activating dopamine D3 receptors and serotonin receptors 5-HT1A, 5-HT2A, and 5-HT1B. The investigation of the effects of antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) appears promising for the treatment of gaming disorder. Neuropeptide systems, particularly endogenous opioids, remain insufficiently studied. The study of the neuropeptides ghrelin, orexin, neurotrophin family peptides, corticotropin-releasing factor (CRF), oxytocin, neuropeptide Y, glucagon-like peptide-1 (GLP-1), and kisspeptin is also considered highly promising. A directed search for peptide targets that influence neurotransmitter systems of the brain may identify critical links for the correction of gambling addiction (pathological gambling) and gaming disorder resulting from excessive computer game use (pathological gaming).

About the authors

Andrei A. Lebedev

Institute of Experimental Medicine; Saint Petersburg State University

Author for correspondence.
Email: aalebedev-iem@rambler.ru
ORCID iD: 0000-0003-0297-0425
SPIN-code: 4998-5204

Dr. Sci. (Biology), Professor

Russian Federation, Saint Petersburg; Saint Petersburg

Sarng S. Pyurveev

Institute of Experimental Medicine; Saint Petersburg State Pediatric Medical University

Email: dr.purveev@gmail.com
ORCID iD: 0000-0002-4467-2269
SPIN-code: 5915-9767

MD, Cand. Sci. (Medicine)

Russian Federation, Saint Petersburg; Saint Petersburg

Konstantin E. Gramota

Institute of Experimental Medicine

Email: konstantin-gramota@yandex.ru
Russian Federation, Saint Petersburg

Elena E. Lyakso

Saint Petersburg State University

Email: lyakso@gmail.com
ORCID iD: 0000-0002-6073-0393
SPIN-code: 8669-2483

Dr. Sci. (Biology), Professor

Russian Federation, Saint Petersburg

Ivan A. Balaganskiy

Institute of Experimental Medicine

Email: balaganskiiivan@mail.ru
ORCID iD: 0009-0002-1752-0785
Russian Federation, Saint Petersburg

Vladimir P. Stetsenko

Institute of Experimental Medicine

Email: stecenko-v@yandex.ru
ORCID iD: 0009-0001-5189-7634
SPIN-code: 2512-4917
Russian Federation, Saint Petersburg

Victor А. Lebedev

Institute of Experimental Medicine

Email: vitya-lebedev-57@mail.ru
ORCID iD: 0000-0002-1525-8106
SPIN-code: 1878-8392

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Eugenii R. Bychkov

Institute of Experimental Medicine

Email: bychkov@mail.ru
ORCID iD: 0000-0002-8911-6805
SPIN-code: 9408-0799

MD, Dr. Sci. (Medicine)

Russian Federation, Saint Petersburg

Petr D. Shabanov

Institute of Experimental Medicine; Saint Petersburg State University

Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-code: 8974-7477

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Saint Petersburg; Saint Petersburg

References

  1. Pyurveev SS, Lebedev AA, Sizov VV, et al. Social isolation induces addictive behavior and increased dopamine release in the nucleus accumbens in response to stimulation of the positive reinforcing zone. Neurosci Behav Physiol. 2025;55(1):211–221. doi: 10.1007/s11055-025-01772-5
  2. Shabanov PD, Arushanyan EB, Bayramov AA, et al. Psychoneuroendocrinology-2024: new development trends. Saint Petersburg; 2025. (In Russ.)
  3. De Brito AMС, de Almeida Pinto MG, Bronstein G, et al. Topiramate combined with cognitive restructuring for the treatment of gambling disorder: A two-center, randomized, double-blind clinical trial. J Gambl Stud. 2017;33(1):249–263. doi: 10.1007/s10899-016-9620-z
  4. Ioannidis K, Del Giovane C, Tzagarakis C, et al. Pharmacological management of gambling disorder: A systematic review and network meta-analysis. Compr Psychiatry. 2025;137:152566. doi: 10.1016/j.comppsych.2024.152566
  5. Mestre-Bach G, Potenza MN. Pharmacological management of gambling disorder: an update of the literature. Expert Rev Neurother. 2024;24(4):391–407. doi: 10.1080/14737175.2024.2316833.
  6. Schmidt C, Skandali N, Gleesborg C, et al. The role of dopaminergic and serotonergic transmission in the processing of primary and monetary reward. Neuropsychopharmacology. 2020;45(9):1490–1497. doi: 10.1038/s41386-020-0702-3
  7. Boileau I, Payer D, Chugani B, et al. The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [11C]-(+)-propyl-hexahydro-naphtho-oxazin and [11C]raclopride. Addiction. 2013;108(5):953–963. doi: 10.1111/add.12066
  8. Barrus MM, Winstanley CA. Dopamine D3 receptors modulate the ability of win-paired cues to increase risky choice in a rat gambling task. J Neurosci. 2016;36(3):785–794. doi: 10.1523/JNEUROSCI.2225-15.2016
  9. Humby T, Smith GE, Small R, et al. Effects of 5-HT2C, 5-HT1A receptor challenges and modafinil on the initiation and persistence of gambling behaviours. Psychopharmacology (Berl). 2020;237(6):1745–1756. doi: 10.1007/s00213-020-05496-x
  10. Seeman P. Parkinson’s disease treatment may cause impulse-control disorder via dopamine D3 receptors. Synapse. 2015;69(4):183–189. doi: 10.1002/syn.21805
  11. Adams WK, Barkus C, Ferland J-MN, et al. Pharmacological evidence that 5-HT(2C) receptor blockade selectively improves decision making when rewards are paired with audiovisual cues in a rat gambling task. Psychopharmacology (Berl). 2017;234(20):3091–3104. doi: 10.1007/s00213-017-4696-4
  12. Pestereva NS, Traktirov DS, Lebedev AА, et al. Fast-scan cyclic voltammetry for measurement of extracellular dopamine release in response to self-stimulation. Reviews on Clinical Pharmacology and Drug Therapy. 2025;23(1):79–90. doi: 10.17816/RCF651161 EDN: ZGMUPG
  13. Antons S, Brand M, Potenza MN. Neurobiology of cue-reactivity, craving, and inhibitory control in non-substance addictive behaviors. J Neurol Sci. 2020;415:116952. doi: 10.1016/j.jns.2020.116952
  14. Macoveanu J, Rowe JB, Hornboll B, et al. Serotonin 2A receptors contribute to the regulation of risk-averse decisions. NeuroImage. 2013;83:35–44. doi: 10.1016/j.neuroimage.2013.06.063
  15. Eagle DM, Baunez C. Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition. Neurosci Biobehav Rev. 2010;34(1):50–72. doi: 10.1016/j.neubiorev.2009.07.003
  16. Faulkner P, Mancinelli F, Lockwood PL, et al. Peripheral serotonin 1B receptor transcription predicts the effect of acute tryptophan depletion on risky decision-making. Int J Neuropsychopharmacol. 2017;20(1):58–66. doi: 10.1093/ijnp/pyw075
  17. Goudriaan AE, Oosterlaan J, de Beurs E, Van den Brink W. Pathological gambling: a comprehensive review of biobehavioral findings. Neurosci Biobehav Rev. 2004;28(2):123–141. doi: 10.1016/j.neubiorev.2004.03.001
  18. Tzschentke TM, Schmidt WJ. Functional relationship among medial prefrontal cortex, nucleus accumbens, and ventral tegmental area in locomotion and reward. Crit Rev Neurobiol. 2000;14(2):131–142. doi: 10.1615/CritRevNeurobiol.v14.i2.20
  19. Youngren KD, Daly DA, Moghaddam B. Distinct actions of endogenous excitatory amino acids on the outflow of dopamine in the nucleus accumbens. J Pharmacol Exp Ther. 1993;264(1):289–293. doi: 10.1016/S0022-3565(25)10266-8
  20. van Huijstee AN, Mansvelder HD. Glutamatergic synaptic plasticity in the mesocortico-limbic system in addiction. Front Cell Neurosci. 2015;8:466. doi: 10.3389/fncel.2014.00466
  21. Rasmussen K. The role of the locus coeruleus and N-methyl-D-aspartic acid (NMDA) and AMPA receptors in opiate withdrawal. Neuropsychopharmacology. 1995;13(4):295–300. doi: 10.1016/0893-133X(95)00082-O
  22. Bespalov AYг, Zvartau EE. Neuropsychopharmacology of NMDA receptor antagonists. Saint Petersburg: Nevsky Dialect; 2000. 297 p. (In Russ.)
  23. Dannon PN, Lowengrub K, Gonopolski Y, et al. Topiramate versus fluvoxamine in the treatment of pathological gambling. Clin Neuropharmacol. 2005;28(1):6–10. doi: 10.1097/01.wnf.0000152623.46474.07
  24. Black DW, McNelly DP, Burke WJ, et al. An open-label trial of acamprosate in the treatment of pathological gambling. Ann Clin Psychiatry. 2011;23(4):250–256. doi: 10.1177/104012371102300403
  25. Gmiro VE, Zhigulin AS. Search for selective GluA1 AMPA receptor antagonists in a series of dicationic compounds. Pharmaceutical Chemistry Journal. 2022;56(3):8–14. doi: 10.30906/0023-1134-2022-56-3-8-14 EDN: ZSRCMD
  26. Potapkin AM, Lebedev AA, Gmiro VE, et al. Study of reinforcing properties of new antagonists of glutamate receptors. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(1):41–47. doi: 10.17816/RCF15141-47 EDN: YJMXLP
  27. Pyurveyev SS, Lebedev AA, Bychkov YeR, et al. Increasing impulsiveness and compulsiveness of animalsin models of addictive behavior when rearingin isolation. Journal of addiction problems. 2024;36(4):41–54. EDN: MVZNVC
  28. Pyurveev SS, Dedanishvili NS, Sekste EA, et al. Early stress in maternal deprivation affects the expression of OX1R in the limbic system of the brain and contributes to the development of anxiety-depressive symptoms in rats. Reviews on Clinical Pharmacology and Drug Therapy. 2024;22(2):153–162. doi: 10.17816/RCF622940 EDN: IPWJTO
  29. Shabanov PD, Lebedev AA. Peptide antagonists of orexin and ghrelin as promising agents for the treatment of addictive disorders. Experimental and Clinical Pharmacology. 2023;86(11S):158. doi: 10.30906/ekf-2023-86s-158 EDN: MNFIZA (In Russ.)
  30. Lebedev AA, Purveev 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. Russian Journal of Physiology. 2023;109(8):1080–1093. doi: 10.31857/S086981392308006X EDN: FCMBCJ
  31. Lebedev AA, Lukashkova VV, Pshenichnaya AG, et al. Emotiogenic effects of antorex, a novel OX1R antagonist, on emotional manifestations of anxiety and compulsiveness in rats. Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(2):151–158. doi: 10.17816/RCF492319 EDN: SGKVIX
  32. Lebedev AA, Karpova IV, Bychkov ER, et al. The ghrelin receptor antagonist [D-Lys3]-GHRP-6 reduces the risk behavior in the rat gambling model by altering the turnover of dopamine and serotonin. Russian Journal of Physiology. 2021;107(9):1100–1111. doi: 10.31857/S0869813921090065
  33. Lebedev AA, Moskalev AR, Abrosimov ME, et al. Effect of neuropeptide Y antagonist BMS193885 on overeating and emotional responses induced by social isolation in rats. Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(2):189–202. doi: 10.17816/RCF192189-202 EDN: OWSTEO
  34. Kern A, Albarran-Zeckler R, Walsh HE, Smith RG. Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron. 2012;73(2):317–332. doi: 10.1016/j.neuron.2011.10.038
  35. Navarro G, Rea W, Quiroz C, et al. Complexes of ghrelin GHS-R1a, GHS-R1b, and dopamine D(1) receptors localized in the ventral tegmental area as main mediators of the dopaminergic effects of ghrelin. J Neurosci. 2022;42(6):940–953. doi: 10.1523/JNEUROSCI.1151-21.2021
  36. Prieto-Garcia L, Egecioglu E, Studer E, et al. Ghrelin and GHS-R1A signaling within the ventral and laterodorsal tegmental area regulate sexual behavior in sexually naive male mice. Psychoneuroendocrinology. 2015;62:392–402. doi: 10.1016/j.psyneuen.2015.09.009
  37. Lebedev AA, Droblenkov AV, Pyurveev SS, et al. Impact of social stress in early ontogenesis on food addiction and ghrelin levels in the hypothalamus of rats. Reviews on Clinical Pharmacology and Drug Therapy. 2024;22(3):309–318. doi: 10.17816/RCF631566 EDN: CKYVNL
  38. Sun Y, Tisdale RK, Kilduff TS. Hypocretin/orexin receptor pharmacology and sleep phases. In: Frontiers of Neurology and Neuroscience. Vol. 45. 2021. P. 22–37. doi: 10.1159/000514963
  39. 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 Addiction Biology. 2023;14(1):48–62. doi: 10.17816/phbn321621 EDN: VIUURH
  40. Lebedev AA, Purveev SS, Nadbitova ND, et al. Antorex, a new antagonist of orexin receptors, reduces binge eating in rats caused by weaning from mother in early ontogenesis. Medical alliance. 2024;12(1):84–90. doi: 10.36422/23076348-2024-12-1-84-90 EDN: GOMVOW
  41. Angelucci F, Martinotti G, Gelfo F, et al. Enhanced BDNF serum levels in patients with severe pathological gambling. Addict Biol. 2013;18(4):749–751. doi: 10.1111/j.1369-1600.2011.00411.x
  42. Kim KM, Choi S-W, Lee J, Kim JW. EEG correlates associated with the severity of gambling disorder and serum BDNF levels in patients with gambling disorder. J Behav Addict. 2018;7(2):331–338. doi: 10.1556/2006.7.2018.43
  43. Solé-Morata N, Baenas I, Etxandi M, et al. The role of neurotrophin genes involved in the vulnerability to gambling disorder. Sci Rep. 2022;12(1):6925. doi: 10.1038/s41598-022-10391-w
  44. Ramadan B, Giustiniani J, Houdayer C, et al. Chronic exposure to glucocorticoids induces suboptimal decision-making in mice. Eur Neuropsychopharmacol. 2021;46:56–67. doi: 10.1016/j.euroneuro.2021.01.094
  45. Pyurveev SS, Lebedev AA, Tsikunov SG, et al. Psychic trauma causes increased impulsivity in a model of gambling addiction by altering dopamine and serotonin metabolism in the prefrontal cortex. Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):329–338. doi: 10.17816/RCF568121 EDN: TPOXSM
  46. Lebedev AA, Pshenichnaya AG, Yakushina ND, et al. Effect of astressin, a corticoliberin antagonist, on aggression and anxiety-fobic states in male rats reared in social isolation. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(3):38–47. doi: 10.17816/RCF15338-47 EDN: ZHRRMB
  47. Georgiou P, Zanos P, Bhat S, et al. Dopamine and stress system modulation of sex differences in decision making. Neuropsychopharmacology. 2018;43(2):313–324. doi: 10.1038/npp.2017.161
  48. Litvinova MV, Tissen IY, Lebedev AA, et al. Influence of oxytocin on the central nervous system by different routes of administration. Psychopharmacology and Addiction Biology. 2023;14(2):139–148. doi: 10.17816/phbn501752 EDN: ANORKE
  49. Zebhauser PT, Macchia A, Gold E, et al. Intranasal oxytocin modulates decision-making depending on outcome predictability — a randomized within-subject controlled trial in healthy males. Biomedicines. 2022;10(12):3230. doi: 10.3390/biomedicines10123230
  50. Bozorgmehr A, Alizadeh F, Sadeghi B, et al. Oxytocin moderates risky decision-making during the Iowa Gambling Task: A new insight based on the role of oxytocin receptor gene polymorphisms and interventional cognitive study. Neurosci Lett. 2019;708:134328. doi: 10.1016/j.neulet.2019.134328
  51. Robinson SL, Bendrath SC, Yates EM, Thiele TE. Basolateral amygdala neuropeptide Y system modulates binge ethanol consumption. Neuropsychopharmacology. 2024;49(4):690–698. doi: 10.1038/s41386-023-01742-w.
  52. Nordin C, Sjödin I. CSF cholecystokinin, gamma-aminobutyric acid and neuropeptide Y in pathological gamblers and healthy controls. J Neural Transm (Vienna). 2007;114(4):499–503. doi: 10.1007/s00702-006-0593-4
  53. Hekim Bozkurt Ö, Güney E, Göker Z, et al. Neuropeptide Y levels in children and adolescents with attention deficit hyperactivity disorder. J Turk Psikiyatri Derg. 2018;29(1):31–35. doi: 10.5080/u22725
  54. Angarita GA, Matuskey D, Pittman B, et al. Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder. Drug Alcohol Depend. 2021;221:108614. doi: 10.1016/j.drugalcdep.2021.108614
  55. Mills EGA, Dhillo WS, Comninos AN. Kisspeptin and the control of emotions, mood and reproductive behaviour. J Endocrinol. 2018;239(1):R1–R12. doi: 10.1530/JOE-18-0269
  56. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614–1627. doi: 10.1056/NEJMoa035322
  57. Heitman LH, Ijzerman AP. G protein-coupled receptors of the hypothalamic-pituitary-gonadal axis: a case for Gnrh, LH, FSH, and GPR54 receptor ligands. Med Res Rev. 2008;28(6):975–1011. doi: 10.1002/med.20129
  58. Aquino NSS, Kokay IC, Perez CT, et al. Kisspeptin stimulation of prolactin secretion requires Kiss1 receptor but not in tuberoinfundibular dopaminergic neurons. Endocrinology. 2019;160(3):522–533. doi: 10.1210/en.2018-00932
  59. Tissen IY, Chepik PA, Lebedev AA, et al. Conditioned place preference of kisspeptin-10. Reviews on Clinical Pharmacology and Drug Therapy. 2021;19(1):47–53. doi: 10.17816/RCF19147-53 EDN: SSEPQB
  60. Pyurveev SS, Lebedev AA, Bychkov ER, Shabanov PD. Pharmacological analysis of the role of kisspeptin-10 in reinforcing mechanisms. Research Results in Pharmacology. 2025;11(1):58–68. doi: 10.18413/rrpharmacology.11.544 EDN: CJJFKT

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