Effect of orexin and its antagonist on the organization of emotional and exploratory behavior of rats in a model of psychic trauma

Abstract

BACKGROUND: A number of recent studies have revealed the role of orexins in regulating emotional behavior and emotional memory. The rationale for this role of orexin regulation is the close bi-directional interaction of orexin neurons with emotional structures of the brain, such as the bed nucleus of the stria terminalis, locus ceruleus, central and dorsomedial amygdala, hippocampus, medial prefrontal cortex. There is experimental and clinical evidence that an endogenous or induced deficiency of orexin effects accelerates the elimination of traumatic memory.

AIM: To study the effect of the OX1R Orexin Receptor Antagonist SB408124 and orexin on the emotional and exploratory behavior of animals after predator-induced stress.

MATERIALS AND METHODS: The experiments were made with 36 male Wistar rats, divided into 4 groups of 8 animals. Animals of 3 groups were exposed to single simulation of post-traumatic stress disorder by exposition with the indian python and subsequent death of one rat as a result of predator activity. The rats of 2 experimental groups received SB408124 OX1R antagonist in a dose of 20 µl of 0.1% solution and Orexin A in the same dose intranasally. The other animals received physiological solution in a dose of 20 µl intranasally. Behavior tests was made 7 days after the modeling of psychotrauma. A panel of behavioral tests was used: an elevated X-maze, an “open field” test, and an “resident–intruder” test. The obtained data were statistically processed using the Student t-test and ANOVA dispersion analysis. The differences were considered statistically significant at p < 0.01.

RESULTS: Orexin antagonist SB408124 showed anxiolytic effects. SB408124 showed anxiolytic properties in stressed rats. It restored the time spent in the light arm of the elevated X-maze to the intact level. In the open field test SB408124 increased (p < 0.01) the orientation behavior and reduced the frequency of freezing in stressed animals. Orexin A suppressed (p < 0,01) locomotor activity of animals in the open field. In the “resident–intruder” test in stressed animals SB408124 restored suppressed communication activity (p < 0,01). Orexin A reduced communicative behavior and increased aggression of animals.

CONCLUSIONS: The work shows a moderate anxiolytic action of SB408124 in the post-traumatic stress model in rats.

Keywords

оrexin / stress / rat / SB408124

References

[1] Tissen IYu, Lebedev AA, Bychkov ER, et al. Orexins and the brain reinforcing systems. Reviews on Clinical Pharmacology and Drug Therapy. 2019;17(4):5–18. (In Russ.) DOI: 10.17816/RCF1745-18

[2] Тиссен И.Ю., Лебедев А.А., Бычков Е.Р., и др. Орексины и подкрепляюшие системы мозга // Обзоры по клинической фармакологии и лекарственной терапии. 2019. Т. 17, № 4. С. 5–18. DOI: 10.17816/RCF1745-18

[3] Tsikunov SG, Makarova TM, Kusov AG, et al. Vliyaniye “chistoy” psikhogennoy travmy na strukturu emotsional’nogo povedeniya krys. Proceedings of the Scientific Conference “Aktual’nyye problemy fundamental’nykh issledovaniy v oblasti biologii i meditsiny” (Saint Petersburg, 2000 Dec 18–20). Saint Petersburg: Nauka; 2000. P. 184–185. (In Russ.)

[4] Цикунов С.Г., Макарова Т.М., Кусов А.Г., и др. Влияние «чистой» психогенной травмы на структуру эмоционального поведения крыс // Материалы научной конференции «Актуальные проблемы фундаментальных исследований в области биологии и медицины», посвящ. 110-летию со дня основания Института экспериментальной медицины (Санкт-Петербург, 18–20 декабря 2000 г.). Санкт-Петербург: Наука, 2000. С. 184–185.

[5] Akanmu MA, Honda K. Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats. Brain Res. 2005;1048(1–2):138–145. DOI: 10.1016/j.brainres.2005.04.064

[6] Akanmu M.A., Honda K. Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats // Brain Res. 2005. Vol. 1048, No. 1–2. P. 138–145. DOI: 10.1016/j.brainres.2005.04.064

[7] Aston-Jones G, Smith RJ, Sartor H, et al. Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction. Brain Res. 2010;1314:74–90. DOI: 10.1016/j.brainres.2009.09.106

[8] Aston-Jones G., Smith R. J., Sartor H., et al. Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction // Brain Res. 2010. Vol. 1314. P. 74–90. DOI: 10.1016/j.brainres.2009.09.106

[9] Arendt DH, Hassell J, Li H, et al. Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. Psychoneuroendocrinology. 2014;40:17–26. DOI: 10.1016/j.psyneuen.2013.10.010

[10] Arendt D.H., Hassell J., Li H., et al. Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala // Psychoneuroendocrinology. 2014. Vol. 40. P. 17–26. DOI: 10.1016/j.psyneuen.2013.10.010

[11] De Lecea L. Hypocretins and the neurobiology of sleep-wake mechanisms. Prog Brain Res. 2012;198:15–24. DOI: 10.1016/B978-0-444-59489-1.00003-3

[12] De Lecea L. Hypocretins and the neurobiology of sleep-wake mechanisms // Prog Brain Res. 2012. Vol. 198. P. 15–24. DOI: 10.1016/B978-0-444-59489-1.00003-3

[13] Gotter AL, Roecker AJ, Hargreaves R, et al. Orexin receptors as therapeutic drug targets. Prog Brain Res. 2012;198:163–188. DOI: 10.1016/B978-0-444-59489-1.00010-0

[14] Gotter A.L., Roecker A.J., Hargreaves R., et al. Orexin receptors as therapeutic drug targets // Prog Brain Res. 2012. P. 163–188. DOI: 10.1016/B978-0-444-59489-1.00010-0

[15] Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 2006;29(10):571–577. DOI: 10.1016/j.tins.2006.08.002

[16] Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function // Trends Neurosci. 2006. Vol. 29, No. 10. P. 571–577. DOI: 10.1016/j.tins.2006.08.002

[17] Herry C, Ciocchi S, Senn V, et al. Switching on and off fear by distinct neuronal circuits. Nature. 2008;454(7204):600–606. DOI: 10.1038/nature07166

[18] Herry C, Ciocchi S, Senn V, et al. Switching on and off fear by distinct neuronal circuits // Nature. 2008. Vol. 454, No. 7204. P. 600–606. DOI: 10.1038/nature07166

[19] Johnson PL, Molosh A, Fitz SD, et al. Orexin, stress, and anxiety/panic states. Prog Brain Res. 2012;198:133–161. DOI: 10.1016/B978-0-444-59489-1.00009-4

[20] Johnson P.L., Molosh A., Fitz S.D., et al. Orexin, stress, and anxiety/panic states // Prog Brain Res. 2012. Vol. 198. P. 133–161. DOI: 10.1016/B978-0-444-59489-1.00009-4

[21] Mieda M, Sakurai T. Overview of orexin/hypocretin system. Prog Brain Res. 2012;198:5–14. DOI: 10.1016/B978-0-444-59489-1.00002-1

[22] Mieda M., Sakurai T. Overview of orexin/hypocretin system // Prog Brain Res. 2012. Vol. 198. P. 5–14. DOI: 10.1016/B978-0-444-59489-1.00002-1

[23] Mikrouli E, Wörtwein G, Soylu R, et al. Increased numbers of orexin/hypocretin neurons in a genetic rat depression model. Neuropeptides. 2011;45(6):401–406. DOI: 10.1016/j.npep.2011.07.010

[24] Mikrouli E., Wörtwein G., Soylu R., et al. Increased numbers of orexin/hypocretin neurons in a genetic rat depression model // Neuropeptides. 2011. Vol. 45, No. 6. P. 401–406. DOI: 10.1016/j.npep.2011.07.010

[25] Myers KM, Davis M. Mechanisms of fear extinction. Mol Psychiatry. 2007;12(2):120–150. DOI: 10.1038/sj.mp.4001939

[26] Myers K.M., Davis M. Mechanisms of fear extinction // Mol Psychiatry. 2007. Vol. 12, No. 2. P. 120–150. DOI: 10.1038/sj.mp.4001939

[27] Ponz A, Khatami R, Poryazova R, et al. Reduced amygdala activity during aversive conditioning in human narcolepsy. Ann Neurol. 2010;67(3):394–398. DOI: 10.1002/ana.21881

[28] Ponz A., Khatami R., Poryazova R., et al. Reduced amygdala activity during aversive conditioning in human narcolepsy // Ann Neurol. 2010. Vol. 67, No. 3. P. 394–398. DOI: 10.1002/ana.21881

[29] Sears RM, Fink AE, Wigestrand MB, et al. Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci USA. 2013;110(50):20260–20265. DOI: 10.1073/pnas.1320325110

[30] Sears R.M., Fink A.E., Wigestrand M.B., et al. Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus // Proc Natl Acad Sci USA. 2013. Vol. 110, No. 50. P. 20260–20265. DOI: 10.1073/pnas.1320325110

[31] Staples LG, Cornish JL. The orexin-1 receptor antagonist SB-334867 attenuates anxiety in rats exposed to cat odor but not the elevated plus maze: An investigation of Trial 1 and Trial 2 effects. Horm Behav. 2014;65(3):294–300. DOI: 10.1016/j.yhbeh.2013.12.014

[32] Staples L.G., Cornish J.L. The orexin-1 receptor antagonist SB-334867 attenuates anxiety in rats exposed to cat odor but not the elevated plus maze: An investigation of Trial 1 and Trial 2 effects // Horm Behav. 2014. Vol. 65, No. 3. P. 294–300. DOI: 10.1016/j.yhbeh.2013.12.014

[33] Tissen I, Kurbanov R, Khohlov P, et al. OX1R antagonist SB408124 action and exyrahypothalamic CRF in rats after psychotraumatic exposure. Georgian Med News. 2019;(290):127–131.

[34] Tissen I., Kurbanov R., Khohlov P., et al. OX1R antagonist SB408124 action and exyrahypothalamic CRF in rats after psychotraumatic exposure // Georgian Med News. 2019. No. 290. P. 127–131.

RIGHTS & PERMISSIONS

Tissen I.Y., Lebedev A.A., Khokhlov P.P., Bychkov E.R., Tsikunov S.G., Shabanov P.D.