Ulyanovsk Medico-biological Journal

PHYSIOLOGY

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DOI 10.34014/2227-1848-2021-1-123-132

 

IMPACT OF EARLY LIFE STRESS ON ANTI-DEPRESSANT SENSITIVITY

 

V.A. Vokina

East-Siberian Institute of Medical and Environmental Research, Angarsk, Russia

 

Long-term consequences of impaired perinatal development are very significant. They appear during the neonatal period and in the first years of life, and persist during ontogenesis. There is little data on the impact of any prenatal factors on the sensitivity of a sexually mature organism to medications.

The aim of the study is to assess the impact of early life stress on the development of individual antidepressant sensitivity.

Materials and Methods. The authors conducted the experiments on sexually mature outbred male rats. To simulate the early life stress, a standard protocol was used. From the 2nd to 15th days of the postnatal period the pup rats were separated from their mother for 3 hours and kept in an incubator. The open-field test, Porsolt test and Sucrose consumption test were used to determine rat’s anxiety level as well as motor, orientation and exploratory activity at puberty. Then, for 14 days, the rats were intragastrically administered with a fluoxetine solution (10 mg/kg/daily), followed by their full examination. Statistical analysis of results was performed using the Mann–Whitney U-test to compare unrelated groups and Wilcoxon's test to compare related groups.

Results. Fluoxetine did not have a pronounced antidepressant effect in animals that survived the early life stress. Such animals demonstrated passive floating during the Porsolt test, without any changes in immobility time. When testing in an open field, a sharp increase in the number of freezing behavior was observed, which was an indicator of an increased anxiety level in animals.

Conclusion. The results obtained indicate that the long-term effects of neonatal stress may be associated with a change in antidepressant sensitivity or an increase in development of unwanted adverse reactions.

Keywords: early life stress, depression, antidepressants, fluoxetine, rats.

Conflict of interest. The author declares no conflict of interest.

 

References

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  26. Kreiss D.S., Lucki I. Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo. J. Pharmacol. Exp. Ther. 1995; 274: 866–876.

  27. Wong M.L., Licinio J. Research and treatment approaches to depression. Nat. Rev. Neurosci. 2001; 2: 343–351.

  28. Santarelli L., Saxe M., Gross C., Surget A., Battaglia F., Dulawa S., Weisstaub N., Lee J., Duman R., Arancio O., Belzung C., Hen R. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003; 301: 805–809.

  29. Kong H., Sha L.L., Fan Y., Xiao M., Ding J.H., Wu J., Hu G. Requirement of AQP4 for antidepressive efficiency of fluoxetine: implication in adult hippocampal neurogenesis. Neuropsychopharmacology. 2009; 34: 1263–1276.

  30. Mateus-Pinheiro A., Pinto L., Bessa J.M., Morais M., Alves N.D., Monteiro S., Patrício P., Almeida O.F., Sousa N. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl. Psychiatry. 2013; 3: e210.

  31. Perera T.D., Dwork A.J., Keegan K.A., Thirumangalakudi L., Lipira C.M., Joyce N., Lange C., Higley J.D., Rosoklija G., Hen R. Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS One. 2011; 6: e17600.

  32. Encinas J.M., Vaahtokari A., Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc. Natl. Acad. Sci. USA. 2006; 103: 8233–8238.

  33. Wang J.W., David D.J., Monckton J.E., Battaglia F., Hen R. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J. Neurosci. 2008; 28: 1374–1384.

  34. Zhou Q.G., Lee D., Ro E., Suh H. Regional-specific effect of fluoxetine on rapidly dividing progenitors along the dorsoventral axis of the hippocampus. Sci. Rep. 2016; 6: 35572.

  35. Alboni S., van Dijk R., Poggini S., Milior G., Perrotta M., Drenth T., Brunello N., Wolfer D.P., Limatola C., Amrein I., Cirulli F., Maggi L., Branchi I. Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. Mol. Psychiatry. 2017; 22: 552–561.

  36. Branchi I. The double edged sword of neural plasticity: increasing serotonin levels leads to both greater vulnerability to depression and improved capacity to recover. Psychoneuroendocrinology. 2011; 36: 339–351.

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Received 07 October 2020; accepted 17 January 2021.

 

Information about the author

Vokina Vera Aleksandrovna, Candidate of Sciences (Biology), Researcher, Laboratory of Bio-modeling and Translational Medicine, East-Siberian Institute of Medical and Environmental Research. 665827, Russia, Irkutsk region, Angarsk, 12A microdistrict, 3; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-8165-8052

 

For citation

Vokina V.A. Vliyanie stressa rannego perioda zhizni na chuvstvitel'nost' organizma k deystviyu antidepressantov [Impact of early life stress on anti-depressant sensitivity]. Ul'yanovskiy mediko-biologicheskiy zhurnal. 2021; 1: 123–132. DOI: 10.34014/2227-1848-2021-1-123-132 (in Russian).

 

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УДК 612.821-053.3:615.214.32]-092.9

DOI 10.34014/2227-1848-2021-1-123-132

 

ВЛИЯНИЕ СТРЕССА РАННЕГО ПЕРИОДА ЖИЗНИ НА ЧУВСТВИТЕЛЬНОСТЬ ОРГАНИЗМА К ДЕЙСТВИЮ АНТИДЕПРЕССАНТОВ

 

В.А. Вокина

ФГБНУ «Восточно-Сибирский институт медико-экологических исследований», г. Ангарск, Россия

 

Отдаленные последствия нарушения перинатального развития весьма значительны и не только проявляются в период новорожденности и в первые годы жизни, но и сохраняются в период онтогенеза. Данные о влиянии каких-либо пренатальных факторов на чувствительность половозрелого организма к действию лекарственных веществ в доступной литературе представлены незначительно.

Цель исследования – оценить роль стресса раннего периода жизни в формировании индивидуальной чувствительности к действию антидепрессантов.

Материалы и методы. Эксперименты проведены на половозрелых беспородных крысах-самцах. Для моделирования стресса раннего периода жизни использовали стандартный протокол, подразумевающий отделение детенышей от матери со 2-го по 15-й дни постнатального периода на 3 ч в условиях инкубатора. В половозрелом возрасте проводили оценку уровня тревожности, двигательной и ориентировочно-исследовательской активности крыс в условиях теста открытого поля, теста Порсолта и теста «Потребление раствора сахарозы». Затем в течение 14 дней крысам внутрижелудочно вводили раствор флуоксетина (10 мг/кг/сут), после чего обследование повторяли в том же объеме. Статистический анализ результатов исследования проводили с использованием U-критерия Манна–Уитни для сравнения несвязанных групп и критерия Вилкоксона для сравнения связанных групп.

Результаты. У животных, переживших стресс раннего периода жизни, флуоксетин не оказывал выраженного антидепрессантного действия. У данных животных в тесте Порсолта преобладало пассивное плавание, без изменения длительности иммобильности. При тестировании в открытом поле наблюдалось резкое повышение числа актов фризинга, что является показателем повышенного уровня тревожности у животных.

Выводы. Полученные результаты свидетельствуют о том, что отдаленные последствия неонатального стресса могут быть связанны с изменением чувствительности к действию антидепрессантов или повышением риска развития нежелательных побочных реакций.

Ключевые слова: стресс раннего периода жизни, депрессия, антидепрессанты, флуоксетин, крысы.

 

Литература

  1. Отеллин В.А., Хожай Л.И., Ватаева Л.А., Шишко Т.Т. Отдаленные последствия воздействия гипоксии в перинатальный период развития на структурно-функциональные характеристики мозга у крыс. Российский физиологический журнал. 2011; 10: 1092–1100.

  2. Nalivaeva N.N., Turner A.J., Zhuravin I.A. Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration. Front. Neurosci. 2018; 12: 825.

  3. Golan H.M., Huleihel M. The effect of prenatal hypoxia on brain development: short- and long-term consequences demonstrated in rodent models. Dev. Sci. 2006; 9 (4): 38–49.

  4. Nathanielsz P.W. Animal models that elucidate basic principles of the developmental origins of adult diseases. ILAR J. 2006; 47 (1): 73–82.

  5. Vehaskari V.M., Woods L.L. Prenatal programming of hypertension: lessons from experimental models. J. Am. Soc. Nephrol. 2005; 16: 2545–2556.

  6. Moritz K.M., Dodic M., Wintour E.M. Kidney development and the fetal programming of adult disease. Bioessays. 2003; 25: 212–220.

  7. Langley-Evans S.C. Developmental programming of health and disease. Proceedings of the Nutrition Society. 2006; 65: 97–105.

  8. Sandman C.A., Davis E.P., Buss C., Glynn L.M. Prenatal programming of human neurological function. International Journal of Peptides. 2011; Article ID 837596.

  9. Самсыгина Г.А. Гипоксическое поражение центральной нервной системы у новорожденных детей: клиника, диагностика, лечение. Педиатрия. 1996; 5: 74–77.

  10. Barkley R.A. Psychosocial treatments for attention deficit / hyperactivity disorder in children. J. Clin. Psychiatry. 2002; 63 (12): 36–43.

  11. Yoshimasu K., Barbaresi W.J., Colligan R.C., Killian J.M., Voigt R.G., Weaver A.L., Katusic S.K. Gender, ADHD, and Reading Disability in a Population Based Birth Cohort. Pediatrics. 2010; 126 (4): 788–795.

  12. Liu Z.W., Yu Y., Lu C., Jiang N., Wang X.P., Xiao S.Y., Liu X.M. Postweaning isolation rearing alters the adult social, sexual preference and mating behaviors of male CD-1 mice. Front. Behav. Neurosci. 2019; 13: 21. DOI: 10.3389/fnbeh.2019.00021.

  13. Lupien S.J., McEwen B.S., Gunnar M.R., Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 2009; 10: 434–445.

  14. Fone K.C., Porkess M.V. Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci. Biobehav. 2008; 32: 1087–1102.

  15. Яузина Н.А., Комлева Ю.К., Салмина А.Б., Петрова М.М., Морозова Г.А., Малиновская Н.А., Герцог Г.Е. Современные экспериментальные модели депрессии. Биомедицина. 2013; 1: 61–71.

  16. Marmendal M., Roman E., Eriksson C.J., Nylander I., Fahlke C. Maternal separation alters maternal care, but has minor effects on behavior and brain opioid peptides in adult offspring. Dev. Psychobiol. 2004; 45 (3): 140–152.

  17. McKinney W.T. Overview of the past contributions of animal models and their changing place in psychiatry. Semin. Clin. Neuropsychiatry. 2001; 6 (1): 68–78.

  18. Marco E.M., Valero M., de la Serna O., Aisa B., Borcel E., Ramirez M.J., Viveros M.P. Maternal deprivation effects on brain plasticity and recognition memory in adolescent male and female rats. Neuropharmacology. 2013; 68: 223–231.

  19. Võikar V., Vasar E., Rauvala H. Behavioral alterations induced by repeated testing in C57BL/6J and 129S2/Sv mice: implications for phenotyping screens. Genes Brain Behav. 2004; 3 (1): 27–38.

  20. Borsini F., Podhorna J., Marazziti D. Do animal models of anxiety predict anxiolytic-like effects of antidepressants. Psychopharmacology. 2002; 163 (2): 121–141.

  21. Farhan M., Haleem D.J. Anxiolytic profile of fluoxetine as monitored following repeated administration in animal rat model of chronic mild stress. Saudi Pharmaceutical Journal. 2016; 24 (5): 571–578.

  22. Данилов Д.С. От флуоксетина до эсциталопрама: сорокалетняя история селективных ингибиторов обратного нейронального захвата серотонина и их значение для клинической практики на современном этапе развития психофармакотерапии депрессий. Дневник психиатра. 2014; 2: 4–7.

  23. Millan M.J. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol. Ther. 2006; 110: 135–370.

  24. Anderson G.M., Barr C.S., Lindell S., Durham A.C., Shifrovich I., Higley J.D. Time course of the effects of the serotonin-selective reuptake inhibitor sertraline on central and peripheral serotonin neurochemistry in the rhesus monkey. Psychopharmacology (Berl.). 2005; 178: 339–346.

  25. Rutter J.J., Gundlah C., Auerbach S.B. Increase in extracellular serotonin produced by uptake inhibitors is enhanced after chronic treatment with fluoxetine. Neurosci. Lett. 1994; 171: 183–186.

  26. Kreiss D.S., Lucki I. Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo. J. Pharmacol. Exp. Ther. 1995; 274: 866–876.

  27. Wong M.L., Licinio J. Research and treatment approaches to depression. Nat. Rev. Neurosci. 2001; 2: 343–351.

  28. Santarelli L., Saxe M., Gross C., Surget A., Battaglia F., Dulawa S., Weisstaub N., Lee J., Duman R., Arancio O., Belzung C., Hen R. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003; 301: 805–809.

  29. Kong H., Sha L.L., Fan Y., Xiao M., Ding J.H., Wu J., Hu G. Requirement of AQP4 for antidepressive efficiency of fluoxetine: implication in adult hippocampal neurogenesis. Neuropsychopharmacology. 2009; 34: 1263–1276.

  30. Mateus-Pinheiro A., Pinto L., Bessa J.M., Morais M., Alves N.D., Monteiro S., Patrício P., Almeida O.F., Sousa N. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl. Psychiatry. 2013; 3: e210.

  31. Perera T.D., Dwork A.J., Keegan K.A., Thirumangalakudi L., Lipira C.M., Joyce N., Lange C., Higley J.D., Rosoklija G., Hen R. Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS One. 2011; 6: e17600.

  32. Encinas J.M., Vaahtokari A., Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc. Natl. Acad. Sci. USA. 2006; 103: 8233–8238.

  33. Wang J.W., David D.J., Monckton J.E., Battaglia F., Hen R. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J. Neurosci. 2008; 28: 1374–1384.

  34. Zhou Q.G., Lee D., Ro E., Suh H. Regional-specific effect of fluoxetine on rapidly dividing progenitors along the dorsoventral axis of the hippocampus. Sci. Rep. 2016; 6: 35572.

  35. Alboni S., van Dijk R., Poggini S., Milior G., Perrotta M., Drenth T., Brunello N., Wolfer D.P., Limatola C., Amrein I., Cirulli F., Maggi L., Branchi I. Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. Mol. Psychiatry. 2017; 22: 552–561.

  36. Branchi I. The double edged sword of neural plasticity: increasing serotonin levels leads to both greater vulnerability to depression and improved capacity to recover. Psychoneuroendocrinology. 2011; 36: 339–351.

  37. Lemaire V., Koehl M., Le Moal M., Abrous D.N. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc. Natl. Acad. Sci. USA. 2000; 97: 11032–11037.

  38. McEwen B.S. Early life influences on life-long patterns of behavior and health. Ment. Retard. Dev. Disabil. Res. Rev. 2003; 9: 149–154.

Поступила в редакцию 07.10.2020; принята 17.01.2021.

 

Автор

Вокина Вера Александровна – кандидат биологических наук, научный сотрудник лаборатории биомоделирования и трансляционной медицины, ФГБНУ «Восточно-Сибирский институт медико-экологических исследований». 665827, Россия, Иркутская обл., г. Ангарск, 12А микрорайон, 3; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-8165-8052

 

Образец цитирования

Вокина В.А. Влияние стресса раннего периода жизни на чувствительность организма к действию антидепрессантов. Ульяновский медико-биологический журнал. 2021; 1: 123–132. DOI: 10.34014/2227-1848-2021-1-123-132.