Semax as a modulator of the psycho-emotional status of rats in an experimental model of depression based on stress

In modern physiology, the priority direction is the study of the influence of various types of stress, leading, as a rule, to the development of depressive states, on the physiological systems of the body. The main methods for assessing the neuroprotective effect, which is the main component of defense against stress, include the study of behavioral reactions that reflect motor, emotional, and cognitive changes. The study of drugs based on regulatory peptides is promising. Semax (ACTH4-7PGP) is a representative of a new synthetic peptide engineering, practically devoid of a hormonal effect and completely preserving the neurotropic activity of adrenocorticotropic hormone. The aim of the work was an experimental study of the effect of semax on the behavior of animals under the influence of experimental depression based on “social” stress. Material and methods. The study was carried out on 50 outbred male rats aged 6 months. Semax effects were studied under conditions of sensory contact - a model of experimental depression based on the formation of aggressive and submissive behavior in animals, using the multicomponent model the Suok test (“ropewalking”) and the Porsolt test to assess the depressive behavior of rats. Results and its discussion. Intermale confrontations led to a decrease in the time spent in the light half of the test, the number of “exploratory” downward glances, directional head movements; a decrease in the number of visited segments in the light section in victims and aggressors. As a whole, the study of behavioral reactions in animals in the Suok test and the Porsolt test in the model of experimental depression (sensory contact) showed the formation of an anxious-depressive state in animals, which was confirmed by a decrease in the motor and exploratory activity of rats. The results were obtained during the Porsolt test, indicating the formation of a depressive state in animals, which was confirmed by an increase in the total period of immobility in both aggressors and victims, an increase in the time of passive swimming, and a decrease in the time of active swimming. With a comprehensive assessment of animal behavior indicators in the Suok test, against the background of a decrease in the level of anxiety under the influence of semax, an improvement in the parameters of exploratory behavior was observed, in the Porsolt test – of motor activity indicators. Conclusions. Investigation of semax effect on the behavioral reactions of animals under conditions of sensory contact indicates that this drug exhibits an anxiolytic and antidepressant effect, eliminating pathological changes in the psycho-emotional status of animals.

1. Yaribeygi H., Panahi Y., Sahraei H., Johnston T.P., Sahebkar A. The impact of stress on body function: A review. EXCLI J. 2017;16:1057–1072. doi: 10.17179/excli2017-480

2. Pershina K.V. Neurophysiological mechanisms of stress and depression and methods of dealing with them. European Science. 2019;(1):78–83. [In Russian].

3. Koolhaas J.M., Boer S.F., Buwalda B., Meerlo P. Social stress models in rodents: Towards enhanced validity. Neurobiol. Stress. 2016;6:104–112. doi: 10.1016/j.ynstr.2016.09.003

4. Yasenyavskaya A.L., Murtaliyeva V.Kh. Social stress as a model of evaluation of efficiency of new stress-protectors. Astrakhanskiy meditsinskiy zhurnal = Astrakhan Medical Journal. 2017;12(2):23–35. [In Russian].

5. Doeselaar L., Yang H., Bordes J., Brix L., Engelhardt C., Tang F., Schmidt M.V. Chronic social defeat stress in female mice leads to sex-specific behavioral and neuroendocrine effects. Stress. 2021;24(2):168–180. doi: 10.1080/10253890.2020.1864319

6. Kolesnikova L.R. Stress-induced changes in the life of the body. Vestnik Smolenskoy gosudarstvennoy meditsinskoy akademii = Vestnik of the Smolensk State Medical Academy. 2018;17(4):30–36. [In Russian].

7. Kolesnikova A.A., Tolstenok I.V., Fleishman M.Yu. Biological effects of proline-containing oligopeptides. Dal’nevostochnyy meditsinskiy zhurnal = Far East Medical Journal. 2021;(4):92–99. [In Russian]. doi: 10.35177/1994-5191-2021-4-19

8. Koroleva S.V., Myasoedov N.F. Semax as a universal drug for therapy and research. Izvestiya Rossiyskoy akademii nauk. Seriya biologicheskaya = Bulletin of the Russian Academy of Science. Division of Biological Science. 2018;(6):669–682. [In Russian]. doi: 10.1134/S000233291806005X

9. Khadartseva K.A., Belyaeva E.A. Semax – application prospects (brief overview message). Klinicheskaya meditsina i farmakologiya = Clinical Medicine and Pharmacology. 2021;7(3):35–37. [In Russian]. doi: 10.12737/2409-3750-2021-7-3-35-37

10. Pozhilova E.V., Novikov V.E. Pharmacodynamics and clinical application of ACTH4-10 neuropeptide. Vestnik Smolenskoy gosudarstvennoy meditsinskoy akademii = Vestnik of the Smolensk State Medical Academy. 2020;19(3):76–86. [In Russian]. doi: 10.37903/vsgma.2020.3.10

11. Yasenyavskaya A.L., Murtalieva V.Kh. Study of the psychotropic effects of Semax on different models of stress. Astrakhanskiy meditsinskiy zhurnal = Astrakhan medical journal. 2017;12(1):72–81. [In Russian].

12. Storozhevykh T.P., Tukhbatova G.R., Senilova Y.E., Pinelis V.G., Andreeva L.A., Myasoedov N.F. Effects of semax and its Pro-Gly-Pro fragment on calcium homeostasis of neurons and their survival under conditions of glutamate toxicity. Bull. Exp. Biol. Med. 2007;143:601–604. doi: 10.1007/s10517-007-0192-x

13. Sharonova I.N., Bukanova Yu.V., Myasoedov N.F., Skrebitsky V.G. Modulation of GABA- and glycine-activated ionic currents with semax in isolated cerebral neurons. Bull. Exp. Biol. Med. 2018;164:612–616. doi: 10.1007/s10517-018-4043-8

14. Polunin G.S., Nurieva S.M., Bayandin D.L., Sheremet N.L., Andreeva L.A. Evaluation of therapeutic effect of new russian drug Semax in optic nerve disease. Vestnik oftal’mologii = The Russian Annals of Ophthalmology. 2000;116(1):15–18. [In Russian].

15. Kudryavtseva N.N. A sensory contact model for the study of aggressive and submissive behaviors in male mice. Aggress. Behav. 1991;17(5):285–291. doi: 10.1002/1098-2337(1991)17:5<285::AIDAB2480170505>3.0.CO;2-P

16. Katel’nikova A.E., Kryshen’ K.L., Zueva A.A., Makarova M.N. Intranasal introduction to laboratory animals. Laboratornyye zhivotnyye dlya nauchnykh issledovaniy = Laboratory Animals for Science. 2019;(2):9. [In Russian]. doi: 10.29296/2618723X-2019-02-09

17. Samotrueva M.A., Teplyy D.L., Tyurenkov I.N. Experimental models of behavior. Yestestvennyye nauki = Natural Sciences. 2009; 27(2):140–152. [In Russian].

18. Porsolt R.D., Anton G., Blavet N., Jalfre M. Behavioural despair in rats: a new model sensitive to antidepressant treatment. Eur. J. Pharmacol. 1978;47(4):379–391. doi: 10.1016/0014-2999(78)90118-8

19. O’Connor D.B., Thayer J.F., Vedhara K. Stress and health: A review of psychobiological processes. Annu. Rev. Psychol. 2021;72:663–688. doi: 10.1146/annurev-psych-062520-122331

20. Lupien S.J., Juster R.P., Raymond C., Marin M.F. The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity. Front. Neuroendocrinol. 2018;49:91–105. doi: 10.1016/j.yfrne.2018.02.001

21. Liu S., Wang Z., Li Y., Sun X., Ge F., Yang M., Wang X., Wang N., Wang J., Cui C. CRFR1 in the ventromedial caudate putamen modulates acute stress-enhanced expression of cocaine locomotor sensitization. Neuropharmacology. 2017;121:60–68. doi: 10.1016/j.neuropharm.2017.04.030

22. Wisłowska-Stanek A., Lehner M., Skórzewska A., Krząścik P., Płaźnik A. Behavioral effects and CRF expression in brain structures of high-and lowanxiety rats after chronic restraint stress. Behavioural Brain Research. 2016;310:26–35. doi: 10.1016/j.bbr.2016.05.001

23. Wisłowska-Stanek A., Płaźnik A., Kołosowska K., Skórzewska A., Turzyńska D., Liguz-Lęcznar M., Krząścik P., Gryz M., Szyndler J., Sobolewska A., Lehner M. Differences in the dopaminergic reward system in rats that passively and actively behave in the Porsolt test. Behavioural Brain Research. 2019;359:181–189. doi: 10.1016/j.bbr.2018.10.027

24. Commons K.G., Cholanians A.B., Babb J.A., Ehlinger D.G. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem. Neurosci. 2017;8(5):955–960. doi: 10.1021/acschemneuro.7b00042

25. McReynolds J.R., Doncheck E.M., Li Y., Vranjkovic O., Graf E.N., Ogasawara D., Cravatt B.F., Baker D.A., Liu Q.-S., Hillard C.J., Mantsch J.R. Stress promotes drug seeking through glucocorticoid-dependent endocannabinoid mobilization in the prelimbic cortex. Biol. Psychiatry. 2018;84(2):85–94. doi: 10.1016/j.biopsych.2017.09.024

26. Lehner M., Gryz M., Wisłowska-Stanek A., Turzyńska D., Sobolewska A., Skórzewska A., Płaźnik A. The amphetamine-associated context exerts a stronger motivational effect in low-anxiety rats than in high-anxiety rats. Behav. Brain Res. 2017;330:97–107. doi: 10.1016/j.bbr.2017.05.012

27. Levitskaya N.G., Kamenskii A.A. Melanocortin system. Uspekhi fiziologicheskikh nauk = Advances in Physiological Sciences. 2009;40(1):44–65. [In Russian].

28. Duval E.R., Javanbakht A., Liberzon I. Neural circuits in anxiety and stress disorders: a focused review. Ther. Clin. Risk Manag. 2015;11:115–126. doi: 10.2147/TCRM.S48528

29. Dodonova S.A., Belykh A.E., Bobyntsev I.I. Regulatory peptides of the melanocortin family: biosynthesis, reception, biological effects. Chelovek i yego zdorov’ye = Man and his Health. 2018;(1):99–108. [In Russian]. doi: 10.21626/vestnik/2018-1/15

30. Kovalev G.I., Sukhorukova N.A., Kondrakhin E.A., Vasil’eva E.V., Salimov R.M. Subchronic administration of Semax increases attention stability in CD-1 mice via modulation of D2-dopamine receptors in the prefrontal cortex. Eksperimental’naya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology. 2021;84(6):3–10. [In Russian]. doi: 10.30906/0869-2092-2021-84-6-3-10