Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences68295610.31857/S0869813925010092UJQBTMEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleEffects of imipramine on anxiety and depressive-like behavior and body weight gain in rats housed in overcrowded conditionsВлияние имипрамина на показатели тревожно-депрессивного поведения и прирост массы тела у крыс при скученностиLosevaE. V.ЛосеваЕ. В.
Russian Federation
losvnd@mail.ruLoginovaN. A.ЛогиноваН. А.
Russian Federation
losvnd@mail.ruPotekhinaA. A.ПотехинаА. А.
Russian Federation
losvnd@mail.ruBroshevitskayaN. D.БрошевицкаяН. Д.
Russian Federation
losvnd@mail.ruKurskayaO. V.КурскаяО. В.
Russian Federation
losvnd@mail.ruZaichenkoM. I.ЗайченкоМ. И.
Russian Federation
losvnd@mail.ruSarkisovaK. Y.СаркисоваК. Ю.
Russian Federation
losvnd@mail.ruInstitute of Higher Nervous Activity and Neurophysiology of the Russian Academy of SciencesИнститут высшей нервной деятельности и нейрофизиологии РАН14012025111113815405062025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/682956

Long-term crowding in rats can lead to anxiety-depressive disorders. Antidepressants, including Imipramine, are used in clinical and experimental settings to correct such states. The aim of this study was to test whether Imipramine has an antidepressant and/or anxiolytic effect on the behavior of rats kept in overcrowded conditions. We studied the effect of daily (4 days before and 10 days during crowding) intraperitoneal injections of Imipramine at a dose of 10 mg/kg on the behavior in tests for anxiety (open field, light-dark, and elevated plus maze – EPM) and in forced swimming test after Imipramine withdrawal (12–15 days of overcrowding) in rats housed in overcrowded (16 rats per cage) and standard (4–5 rats per cage) conditions. Also, body weight gain on days 8 and 12 of overcrowding and the blood plasma corticosterone level on day 16 of overcrowding were assessed in the same groups of rats. Overcrowding led to activation of behavioral reactions in the light-dark and EPM tests, which did not decrease (with the exception of three indicators) after Imipramine treatment. So, Imipramine did not have a significant corrective effect in these tests on the behavior of rats kept in overcrowded conditions. In the forced swimming test under overcrowded conditions, an increase in immobility was observed, and imipramine led to the correction of this disorder. Body weight gain decreased after treatment of Imipramine in standard and overcrowded (to a greater degree) conditions, which may indicate a negative side effect of the antidepressant. The level of corticosterone in blood plasma did not differ in rats kept in overcrowded and standard conditions and did not change under the influence of Imipramine. Thus, the antidepressant Imipramine had a therapeutic effect on increased immobility in the forced swim test in rats under overcrowded conditions. This suggests that the behavioral changes observed in this test in rats under crowded conditions are depressive-like behavioral disorders. That is, imipramine had a pronounced antidepressant effect in the forced swimming test.

Долговременная скученность у крыс может приводить к тревожно-депрессивным расстройствам. Антидепрессанты, в том числе имипрамин, применяются в клинике и эксперименте для коррекции таких состояний. Цель настоящей работы – проверить, окажет ли имипрамин антидепрессантный и/или анксиолитический эффект на поведение крыс при скученности. Исследовали у крыс при скученности (16 крыс в клетке) и стандартном (4–5 крыс в клетке) содержании влияние ежедневного (4 дня до и 10 дней во время скученности) введения имипрамина в дозе 10 мг/кг на поведение в тестах открытое поле, свет-темнота, приподнятый крестообразный лабиринт (ПКЛ) и вынужденное плавание после отмены имипрамина (12–15-е дни скученности). Также оценивали прирост массы тела у тех же групп крыс на 8- и 12-е дни скученности и уровень кортикостерона в плазме крови на 16-й день скученности. Имипрамин в стандартных условиях не изменял поведение крыс во всех тестах. Скученность приводила к активации поведенческих реакций в тестах свет-темнота и ПКЛ, которая не уменьшалась (за исключением трех показателей) при действии имипрамина. То есть имипрамин не оказал выраженного корректирующего влияния в этих тестах на поведение крыс, содержавшихся в условиях скученности. В тесте вынужденного плавания скученность вызывала повышение иммобильности, а имипрамин приводил к коррекции этого нарушения. Под действием имипрамина в стандартных условиях и при скученности (в большей степени) уменьшался прирост массы тела, что свидетельствует о негативном побочном эффекте антидепрессанта. Уровень кортикостерона в плазме крови не отличался у крыс при стандартном и скученном содержании и не изменялся под воздействием имипрамина. Таким образом, антидепрессант имипрамин оказал терапевтическое воздействие на повышенную иммобильность в тесте вынужденного плавания у крыс при скученности. Это дает основание считать, что изменения поведения, наблюдаемые в этом тесте у крыс при скученности, являются депрессивно подобными поведенческими нарушениями. То есть имипрамин оказал выраженный антидепрессантный эффект в тесте вынужденного плавания.

Wistar ratsovercrowded housingantidepressants Imipramineanxiety testsforced swimming testbody weight gainplasma corticosterone levelкрысы Wistarскученностьантидепрессант имипраминтесты на тревожностьтест вынужденного плаванияприрост массы телакортикостеронМинистерство науки и высшего образования Российской ФедерацииMinistry of Science and Higher Education of the Russian FederationЛосева ЕВ (2021) Психосоциальный стресс перенаселенности (скученности): негативные последствия для организма человека и грызунов. Интеграт физиол 2: 33–40. [Loseva EV (2021) Psychosocial stress of overcrowding: negative consequences for humans and rodents. Integrat Physiol 22: 33–40. (In Russ)]. https://www.doi.org/10.33910/2687-1270-2021-2-1-33-40López-Muñoz F, Alamo C (2009) Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des 15: 1563–1586. https://www.doi.org/10.2174/138161209788168001Brown WA, Rosdolsky M (2015) The clinical discovery of imipramine. Am J Psychiatr 172(5): 426–429. https://doi.org/10.1176/appi.ajp.2015.14101336Volz HP, Laux G (2022) Tricyclics: Imipramine, Clomipramine, Trimipramine (Dibenzazepines). In: Riederer P, Laux G, Nagatsu T, Le W, Riederer C (eds) Neuropsychopharmacotherapy. Springer Cham. 1–11. https://doi.org/10.1007/978-3-319-56015-1_385-1Fayez R, Gupta V (2024) Imipramine. [Updated 2023 May 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557656/Campos-Cardoso R, Silva CPB, Carolino ROG, Anselmo-Franci JA, Tirapelli CR, Padovan CM (2021) Imipramine attenuates anxiety- and depressive-like effects of acute and prolonged ethanol-abstinence in male rats by modulating SERT and GR expression in the dorsal hippocampus. Behav Brain Res 408: 113295. https://doi.org/10.1016/j.bbr.2021.113295Possamai-Della T, Dal-Pont GC, Resende WR, Aguiar-Geraldo JM, Peper-Nascimento J, Quevedo J, Valvassori SS (2022) Imipramine can be effective on depressive-like behaviors, but not on neurotrophic factor levels in an animal model for bipolar disorder induced by ouabain. Mol Neurobiol 59: 7170–7181. https://doi.org/10.1007/s12035-022-03022-ySarkisova KY, Midzianovskaia IS, Kulikov MA (2003) Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy. Behav Brain Res 144: 211–226. https://doi.org/10.1016/s0166_4328(03)00090_1Ramirez K, Shea DT, McKim DB, Reader BF, Sheridan JF (2015) Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun 46: 212–220. https://doi.org/10.1016/j.bbi.2015.01.016Ramirez K, Sheridan JF (2016) Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive- like behaviors. Brain Behav Immun 57: 293–303. https://doi.org/10.1016/j.bbi.2016.05.008Mavissakalian M, Perel J, Guo S (2002) Specific side effects of long-term imipramine management of panic disorder. J Clin Psychopharmacol 22: 155–161. https://doi.org/10.1097/00004714-200204000-00008Sarkisova KY, Gabova AV, Fedosova EA, Shatskova AB, Narkevich VB, Kudrin VS (2023) Antidepressant and anxiolytic effects of L-Methionine in the WAG/RIJ rat model of depression comorbid with absence epilepsy. Int J Mol Sci 24: 12425. https://doi.org/10.3390/ijms241512425Bonda C, Pawar S, Lokhande J (2017) Evaluation of antidepressant activity of tramadol in comparison with imipramine in Swiss albino mice. Int J Basic Clin Pharmacol 6: 695–699. https://doi.org/10.18203/2319-2003.ijbcp20170839Ramos A, Pereira E, Martins GC, Wehrmeister TD, Izídio GS (2008) Integrating the open field, elevated plus maze and light/dark box to assess different types of emotional behaviors in one single trial. Behav Brain Res 193: 277–288. https://doi.org/10.1016/j.bbr.2008.06.007Loseva EV, Loginova NA, Russu LI, Mezentseva MV (2022) Behavior of rats in tests for anxiety after a short intranasal injection of single-walled carbon nanotubes in two small doses. J Evol Biochem Phys 58: 1973–1986. https://doi.org/10.1134/S0022093022060254Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730–732. https://doi.org/10.1038/266730a0Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29: 547–569. https://doi.org/10.1016/j.neubiorev.2005.03.008Sarkisova KYu, Kulikov MA (2006) Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenic seizures. Behav Brain Res 166: 9–18. https://doi.org/10.1016/j.bbr.2005.07.024Sarkisova K, van Luijtelaar G (2011) The WAG/Rij strain: A genetic animal model of absence epilepsy with comorbidity of depression. Prog Neuropsychopharmacol Biol Psychiatr 35: 854–876. https://doi.org/10.1016/j.pnpbp.2010.11.010Loginova NA, Loseva EV, Sarkisova KYu, Kudrin VS (2023) Effects of interferon-α on depressive-like behavior and brain neurochemistry in rats housed in standard and overcrowding conditions. J Evol Biochem Phys 59: 2005–2021. https://doi.org/10.1134/S0022093023060108Broshevitskaya ND, Pavlova IV, Zaichenko MI, Gruzdeva VA, Grigoryan GA (2021) Effects of early proinflammatory stress on anxiety and depression-like behavior in rats of different ages. Neurosci Behav Physiol 51: 390–401. https://doi.org/10.1007/s11055-021-01083-5Calvano SE, Reynolds RW (1984) Circadian fluctuations in plasma corticosterone, corticosterone-binding activity and total protein in male rats: possible disruption by serial blood sampling. Endocr Res 10(1): 11–25. https://doi.org/10.1080/07435808409046762. PMID: 6745208D'Agostino J, Vaeth GF, Henning SJ (1982) Diurnal rhythm of total and free concentrations of serum corticosterone in the rat. Acta Endocrinol (Copenh) 100(1): 85–90. https://doi.org/10.1530/acta.0.1000085. PMID: 7202315Kudryavtseva NN, Shurlygina AV, Galyamina AG, Smagin DA, Kovalenko IL, Popova NA, Nikolin VP, Ilnitskaya SI, Melnikova EV, Trufakin VA (2019) Immunopathology of mixed anxiety/depression disorders: an experimental approach to studies of immunodeficiency states (review). Neurosci Behav Physiol 49: 384–398. https://doi.org/10.1007/s11055-019-00745-9Ressler KJ, Nemeroff CB (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12 Suppl 1: 2–19. https://doi.org/10.1002/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2–4Latanov AV, Korshunov VA, Maiorov VI, Serkov AN (2019) Serotonin and Dopamine in Biological Models of Depression. Neurosci Behav Physiol 49: 987–996. https://doi.org/10.1007/s11055-019-00828-7Pilipović I, Stojić-Vukanić Z, Leposavic GM (2023) Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis. Pharmacol Therap 243(Pt 1): 108358. https://doi.org/10.1016/j.pharmthera.2023.108358Uarquin DG, Meyer JS, Cardenas FP, Rojas MJ (2016) Effect of overcrowding on hair corticosterone concentrations in juvenile male Wistar rats. J Am Assoc Lab Anim Sci 55(6): 749–755. PMID: 27931312; PMCID: PMC5113875Gądek-Michalska A, Bugajski A, Tadeusz J, Rachwalska P, Bugajski J (2017) Chronic social isolation in adaptation of HPA axis to heterotypic stress. Pharmacol Rep 69: 1213–1223. https://doi.org/10.1016/j.pharep.2017.08.011Gavrilov VV, Onufriev MV, Moiseeva YV, Alexandrov YI, Gulyaeva NV (2022) Chronic social isolation stress and crowding in rats have different effects on learning an operant behavior and the state of the hypothalamo-hypophyseal-adrenocortical system. Neurosci Behav Physiol 52: 698–704. https://doi.org/10.1007/s11055-022-01295-3Хлебникова НН, Крупина НА (2017) Экспериментальное тревожно-депрессивное состояние у крыс, вызванное неонатальным действием ингибитора дипептидилпептидазы-IV дипротина А: эффекты имипрамина. Патол физиол экспер терапия 61(4): 4–12. [Khlebnikova NN, Krupina NA (2017) Experimental anxiety-depressive state in rats caused by neonatal exposure to the inhibitor of dipeptidyl peptidase IV, diprotin A: effects of imipramine. Pathol Physiol Exp Therapy 61(4): 4–12. (In Russ)]. https://doi.org/10.25557/IGPP.2017.4.8517Knyazeva SI, Loginova NA, Loseva EV (2012) Anxiety level and body weight changes in rats living in overpopulated cages. Bull Exp Biol Med 154(1): 3–6. https://doi.org/10.1007/s10517-012-1860-zMogensen J, Pedersen TK, Holm S (1994) Effects of chronicimipramine on exploration, locomotion, and food/water intake in rats. Pharmacol Biochem Behav 47(3): 427–435. https://doi.org/10.1016/0091-3057(94)90139-2Лосева ЕВ, Логинова НА, Потехина АА, Федосова ЕА, Саркисова КЮ (2022) Воздействие имипрамина на тревожно-депрессивное поведение и привес массы тела у крыс при стандартном и скученном содержании. Интеграт физиол Всерос конф междунар участием, тезисы докл СПб. Ин-т физиол им ИП Павлова РАН 7–9 дек. 125. [Loseva EV, Loginova NA, Potekhina AA, Fedosova EA, Sarkisova KYu (2022) Effect of imipramine on anxiety-depressive behavior and body weight gain in rats under standard and crowded conditions. Integrative physiology. All-Russian confer with internat participat, abstracts of reports. St. Petersburg. Pavlov Institute Physiol RAS. December 7–9. 125. (In Russ)]. ISBN 978-5-4386-2232-1Loseva EV, Loginova NA, Potekhina AA, Fedosova EA, Sarkisova KYu, Broshevitskaya ND, Zaichenko MI (2023) Influence of the antidepressant imipramine on behavior in tests for anxiety and depression, body weight gain and blood corticosterone level in rats kept at subchronic overcrowding. Neuroscie Med Psychol. ХIX Internat Interdisciplin Congr, Abstracts Rep. Sudak, Crimea, Russia, May 30 – June 10. MAKS-Press LLC Moscow. 179–180. (In Russ, in Engl). https://doi.org/10.29003/m3292.sudak.ns2023-19/179-180