Effect of the dipeptide retro-analog of cholecystokinin tetrapeptide (GB-115) on the behavior of rhesus monkeys in isolation

DOI: https://doi.org/10.29296/24999490-2023-06-03

Al.V. Panchenko(1), An.V. Panchenko(1), L.E. Pavlova(1), M.F. Timina(1), E.V. Cherkashina(1), L.G. Kolik2, S.B. Seredenin2
1-Research Institute of Medical Primatology, st. Mira, p. 177, p. Vesele, Adler district, Sochi, Krasnodar region, 354376, Russian Federation;
2-Research Institute of Pharmacology named after. V.V. Zakusova, st. Baltiyskaya, 8, Moscow, 125315, Russian Federation

Introduction. The developed domestic dipeptide retro-analog of cholecystokinin (CCK) tetrapeptide (N-(6-phenylhexanoyl)-glycyltryptophan amide, compound GB-115) with antagonistic properties towards CCK1 receptors has anxiolytic activity, previously shown in preclinical and clinical studies. Purpose of the study. Evaluation of the anxiolytic effect of GB-115 in tablet dosage form with subchronic oral administration in comparison with phenazepam in laboratory primates. Methods. The experiment was performed on four male rhesus monkeys (Macaca mulatta) aged 5.7–6.7 years. After a 30-day period of adaptation to the conditions of individual housing, an experiment was performed with GB-115 (0.001 g tablets) and then with phenazepam (0.0005 g tablets). Both drugs were given one at a time (7 days), and then 2 tablets (7 days). Behavior was assessed by observing the object with registration according to the “Yes-No” principle of ethogram elements in the background periods, during the administration of drugs and during their withdrawal. Using enzyme immunoassay, the content of stress response biomarkers: cortisol and dehydroepiandrosterone sulfate (DHEA-S) was determined in blood serum. Results. GB-115 (0.001 g each) and phenazepam (0.001 g each) reduced the stay of animals in the upper part of the cage compared to the background period, which indicates a decrease in the stress response. GB-115 (0.002 g each) decreased the cortisol/DHEA-S ratio. Phenazepam dose-dependently reduced serum cortisol levels without affecting DHEA-S levels; with the administration of phenazepam (0.001 g), a decrease in the cortisol/DHEA-S ratio was also recorded. Conclusion. A positive effect of GB-115, when administered subchronically, on the weakening of the emotional stress reaction and restoration of adaptive behavior in rhesus monkeys was revealed, comparable to the effect of phenazepam, which confirms the possibility of using blockade of CCK1 receptors as one of the approaches for the treatment of anxiety disorders.
Keywords: 
cortisol, dehydroepiandrosterone, stress, GB-115, phenazepam, rhesus monkeys
Список литературы: 
  1. Rehfeld J.F. Cholecystokinin and panic disorder: Reflections on the history and some unsolved questions. Mol Basel Switz. 2021; 26 (18): 5657. DOI: 10.3390/molecules26185657
  2. Гудашева Т.А., Кирьянова Е.П., Колик Л.Г., Константинопольский М.А., Середенин С.Б. Дизайн и синтез дипептидных аналогов холецистокинина-4 с анксиолитической и анксиогенной активностью. Биоорганическая Химия. 2007; 33 (4): 413–20. DOI: 10.1134/s1068162007040036
  3. [Gudasheva T.A., Kir’ianova E.P., Kolik L.G., Konstantinopol’skii M.A., Seredenin S.B. Design and synthesis of cholecystokinin-4 dipeptide analogues with anxiolytic and anxiogenic activities. Bioorg Khim. 2007; 33 (4): 413–20 (in Russian). DOI: 10.1134/s1068162007040036]
  4. Kolik L., Gudasheva T.A., Seredenin S.B. P.4.004 Dipeptide anxiolytic GB-115: new receptor targets. Eur Neuropsychopharmacol. 2011; 21: 146–7. DOI: 10.1016/S0924-977X(11)70177-8
  5. Колик Л.Г., Гудашева Т.А., Середенин С.Б. Об участии холецистокининовой системы в реализации анксиолитических эффектов дипептида ГБ-115. Бюллетень экспериментальной биологии и медицины. 2012; 153 (6): 828–32.
  6. [Kolik L.G., Gudasheva T.A., Seredenin S.B. Role of the cholecystokinin system in anxiolytic activity of dipeptide GB-115. Bull Exp Biol Med. 2012; 153 (6): 828–32. DOI:10.1007/s10517-012-1842-1]
  7. Колик Л.Г., Жуков В.Н., Середенин С.Б. Характер проявления антиноцицептивных и анксиолитических свойств соединения ГБ-115 в аспекте взаимодействия холецистокининовой и опиоидергической систем. Экспериментальная и клиническая фармакология. 2007; 70 (2): 8–11.
  8. [Kolik L.G., Zhukov V.N., Seredenin S.B. Manifestations of the antinociceptive and anxiolytic properties of the compound GB-115: interactions of cholecystokinin and opioid systems. Eksp Klin Farmakol. 2007; 70 (2): 8–11 (in Russian)]
  9. Колик Л.Г., Константинопольский М.А., Рыбина И.В., Поварнина П.Ю., Гудашева Т.А., Середенин С.Б. Анксиолитическая активность дипептида ГБ-115 при пероральном введении. Бюллетень экспериментальной биологии и медицины. 2013; 155 (2): 163–6.
  10. [Kolik L.G., Konstantinopolsky M.A., Ryibina I.V., Povarnina P.Y., Gudasheva T.A., Seredenin S.B. Anxiolytic activity of dipeptide GB-115 after oral administration. Bull Exp Biol Med. 2013; 155 (2): 163–6. DOI: 10.1007/s10517-013-2112-6 (in Russian)]
  11. Литвин А.А., Шевченко Р.В., Колыванов Г.Б., Бочков П.О., Смирнов В.В., Раскин С.Ю., Грибакина О.Г., Жердев В.П., Колик Л.Г., Гудашева Т.А., Ивашкина Н.Ю. Оценка периода полувыведения коротких пептидных препаратов у человека по результатам фармакокинетического исследования на животных. Химико-фармацевтический журнал. 2019; 53 (8): 16–9. DOI: 10.30906/0023-1134-2019-53-8-16-19
  12. [Litvin A.A., Shevchenko R.V., Kolyvanov G.B., Bochkov P.O., Smirnov V.V., Raskin S.Yu., Grybakina O.G., Zherdev V.P., Kolik L.G., Gudasheva T.A., Ivashkina N. Yu. Interspecies extrapolation of the half-life of short peptide drugs: From animal to human pharmacokinetics. Khimiko-Farmatsevticheskii Zhurnal. 2019; 53 (8): 16–9. DOI:10.30906/0023-1134-2019-53-8-16-19 (in Russian)]
  13. Camus S.M.J, Blois-Heulin C., Li Q., Hausberger M., Bezard E. Behavioural profiles in captive-bred cynomolgus macaques: Towards monkey models of mental disorders? PLoS ONE. 2013; 8 (4): e62141. DOI: 10.1371/journal.pone.0062141
  14. Незнамов Г.Г., Дорофеева О.А., Метлина М.В., Сюняков Т.С., Минаев С.В., Ивашкина Н.Ю., Мартьянов В.А., Середенин С.Б. Результаты клинического исследования нового анксиолитика, блокатора центральных холецистокининовых рецепторов. Журнал неврологии и психиатрии им. C.C. Корсакова. 2019; 119 (8): 53–60. DOI: 10.17116/jnevro201911908153
  15. [Neznamov G.G., Dorofeeva O.A., Metlina M.V., Syunyakov T.S., Minaev S.V., Ivashkina N.Yu., Martyanov V.A., Seredenin S.B. Results of a clinical study of a new anxiolytic, a blocker of central cholecystokinin receptors. Zhurnal Nevrol Psikhiatrii Im SS Korsakova. 2019; 119 (8): 53–60. DOI: 10.17116/jnevro201911908153 (in Russian)]
  16. Середенин С.Б., Воронина Т.А., Незнамов Г.Г., Жердев В.П. Феназепам: 25 лет в медицинской практике. М.: Наука, 2007; 382.
  17. [Seredenin S.B., Voronina T.A., Neznamov G.G., Zherdev V.P. Phenazepam: 25 years in medical practice. M.: Nauka, 2007; 382 (in Russian)]
  18. Harro J., Põld M., Vasar E. Anxiogenic-like action of caerulein, a CCK-8 receptor agonist, in the mouse: influence of acute and subchronic diazepam treatment. Naunyn-Schmiedeberg’s Arch Pharmacol. 1990; 341: 62–7. DOI:10.1007/BF00195059
  19. 12. Maestripieri D., Schino G., Aureli F., Troisi A. A modest proposal: displacement activities as an indicator of emotions in primates. Anim Behav. 1992; 44 (5): 967–79. DOI: 10.1016/S0003-3472(05)80592-5
  20. Baker K.C. Cage position and response to humans in singly-housed rhesus macaques (Macaca mulatta). J Am Assoc Lab Anim Sci. 2020; 59 (5): 503–7. DOI: 10.30802/AALAS-JAALAS-19-000115
  21. Lutz C.K., Coleman K., Worlein J., Novak M.A. Hair loss and hair-pulling in rhesus macaques (Macaca mulatta). J. Am. Assoc Lab Anim Sci JAALAS. 2013; 52 (4): 454–7.
  22. Lutz C., Well A., Novak M. Stereotypic and self-injurious behavior in rhesus macaques: A survey and retrospective analysis of environment and early experience. Am. J. Primatol. 2003; 60 (1): 1–15. DOI: 10.1002/ajp.10075
  23. Goncharova N.D. The HPA axis under stress and aging: Individual vulnerability is associated with behavioral patterns and exposure time. BioEssays. 2020; 42 (9): 2000007. DOI:10.1002/bies.202000007
  24. Griebel G., Perrault G., Sanger D.J. CCK receptor antagonists in animal models of anxiety: Comparison between exploration tests, conflict procedures and a model based on defensive behaviours. Behav Pharmacol. 1997; 8 (6): 549–60. DOI: 10.1097/00008877-199711000-00013
  25. Kоhler C., Chan-Palay V. Cholecystokinin-octapeptide (CCK-8) receptors in the hippocampal region: a comparative in vitro autoradiographic study in the rat, monkey and the postmortem human brain. Neurosci Lett. 1988; 90 (1–2): 51–6. DOI: 10.1016/0304-3940(88)90785-9
  26. Leranth C., Frotscher M., Rakic P. CCK-immunoreactive terminals form different types of synapses in the rat and monkey hippocampus. Histochemistry. 1988; 88 (3–6): 343–52. DOI: 10.1007/BF00570293
  27. Staljanssens D., Azari E.K., Christiaens O., Beaufays J., Lins L., Van Camp J., Smagghe G. The CCK(-like) receptor in the animal kingdom: Functions, evolution and structures. Peptides. 2011; 32 (3): 607–19. DOI: 10.1016/j.peptides.2010.11.025