We studied the influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. Both single and chronic administration of imipramine potently shortened immobility in naive rats during forced-swim testing. However, chronic, 14-day forced-swim stress testing blocked the immobility-decreasing effect induced by a single administration of imipramine. When imipramine was administered for 14 days concurrently with forced-swim stress testing, immobility was shortened significantly. From the viewpoint of imipramine's effect, these findings suggest that chronic forced-swim stress testing in rats may be an effective animal model for depression.</p

Araki, Hiroaki

Gomita, Yutaka

Kitamura, Yoshihisa

Nagatani, Tadashi

Shibata, Kazuhiko

Takao, Katsuyuki

English

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 58, Issue 6 2004 Article 3DECEMBER 2004Influence of imipramine on the duration ofimmobility in chronic forced-swim-stressedrats.Yoshihisa Kitamura∗ Hiroaki Araki† Tadashi Nagatani‡Katsuyuki Takao∗∗ Kazuhiko Shibata†† Yutaka Gomita‡‡∗Okayama University,†&#xFEFF;Ehime University Hospital,‡Asahi Kasei Co.,∗∗Asahi Kasei Co.,††Okayama University,‡‡Okayama University,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Influence of imipramine on the duration ofimmobility in chronic forced-swim-stressedrats.∗Yoshihisa Kitamura, Hiroaki Araki, Tadashi Nagatani, Katsuyuki Takao,Kazuhiko Shibata, and Yutaka GomitaAbstractWe studied the influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. Both single and chronic administration of imipramine potently shortened immobilityin naive rats during forced-swim testing. However, chronic, 14-day forced-swim stress testingblocked the immobility-decreasing effect induced by a single administration of imipramine. Whenimipramine was administered for 14 days concurrently with forced-swim stress testing, immobilitywas shortened significantly. From the viewpoint of imipramine’s effect, these findings suggest thatchronic forced-swim stress testing in rats may be an effective animal model for depression.KEYWORDS: stress, depression, imipramine, forced-swim test, animal model∗PMID: 15762295 [PubMed - indexed for MEDLINE]Copyright (C) OKAYAMA UNIVERSITY MEDICAL SCHOOL Inﬂuence of Imipramine on the Duration of Immobility in Chronic Forced-Swim-Stressed Rats Yoshihisa Kitamura???, Hiroaki Araki?, Tadashi Nagatani?, Katsuyuki Takao?,Kazuhiko Shibata?, and Yutaka Gomita??Department of Hospital Pharmacy, Okayama University Medical School, Okayama 700-8558, Japan,?Division of Pharmacy, Misasa Medical Center, Okayama University Medical School, Tottori 682-0192, Japan,?Department of Hospital Pharmacy, Ehime University Hospital, Ehime 791-0295, Japan, and?Health Care R&D Control Department, Asahi Kasei Co., Tokyo 101-8481, Japan We studied the inﬂuence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. Both single and chronic administration of imipramine potently shortened immobility in naı?ve rats during forced-swim testing. However, chronic, 14-day forced-swim stress testing blocked the immobility-decreasing eﬀect induced by a single administration of imipramine. When imipramine was administered for 14 days concurrently with forced-swim stress testing, immobility was shortened signiﬁcantly. From the viewpoint of imipramine’s eﬀect, these ﬁndings suggest that chronic forced-swim stress testing in rats may be an eﬀective animal model for depression.Key words: stress, depression, imipramine, forced-swim test, animal model S tress has been suggested to be an important etiological factor in many psychiatric diseases,including aﬀective disorders. The main target of stress research in the central nervous system is the monoaminer-gic system, and stress is reported to aﬀect the function of brain monoaminergic receptors. In particular, serotonin(5-HT)receptors have been postulated to play an impor-tant role in the pathogenesis of aﬀective disorders.Several studies have found elevated numbers of 5-HT?receptors in the post-mortem brains of suicide victims and depressed subjects［1-3］. In animal studies, the number of 5-HT?receptors is decreased in the rat frontal cortex following the chronic administration of antidepressants［4-5］. These ﬁndings suggest that the down-regulation of 5-HT? receptors may be related to the activity of antidepressants.Previously, we developed an animal model for depres-sion that exposed rats to chronic forced-swim stress testing for 14 days［6］. In that study, rats were individu-ally forced to swim for 6 min in plastic cylinders. For the chronic tests, they were forced to swim once daily for 14 days. The chronic forced-swim stress test increased the number of frontal cortical 5-HT? receptors without altering the concentrations of 5-HT and 5-hydroxyindole acetic acids or the number of wet-dog shakes mediated by 5-HT?receptors. These results suggested that 5-HT?receptors are closely related to the rat’s response to chronic forced-swim stress testing, which may therefore act as a model of depressive conditions in animals.However, previously we did not study the eﬀect of antidepressants on chronic forced-swim stress in rats. As antidepressants possess broad therapeutic properties, in the present study we examined their eﬃcacy in chronic forced-swim stress testing, an animal model of depres-Received April 8,2004;accepted July 5,2004.?Corresponding author.Phone:＋81-86-235-7650;Fax:＋81-86-235-7796 E-mail:ykita＠cc.okayama-u.ac.jp(Y.Kitamura)http://www.lib.okayama-u.ac.jp/www/acta/Acta Med. Okayama, 2004 Vol. 58, No. 6, pp. 271-274 Short Communication Copyright?ｃ2004 by Okayama University Medical School.1Kitamura et al.: Influence of imipramine on the duration of immobility inProduced by The Berkeley Electronic Press, 2004sion.In rodents, the forced-swim test is widely used to predict the activity of antidepressants in naı?ve rats［7］.Imipramine is a well-established tricyclic antidepressant that has been used clinically for many years. In animal studies, it is well known that both the single and chronic administration of imipramine reduces the duration of immobility in rats during forced-swim tests［7, 8］.However, these studies used naı?ve rats;there have been few attempts to examine imipramine’s chronic eﬀects in rats after chronic forced-swim stress testing. Therefore,we examined the inﬂuence of chronic forced-swim stress testing, which may be a model of depressive conditions in animals, on imipramine’s eﬀect on the duration of im-mobility in those tests.Materials and Methods Male Wistar rats (Charles River,Yokohama, Japan)weighing 180-230 g, and kept on a constant light-dark cycle (light 07:00-19:00 h), were sustained with standard laboratory food and tap water in an air-conditioned room(23±1°C with approximately 60 humidity).The drug used in this study was imip-ramine hydrochloride (Wako Pure Chemicals, Osaka,Japan). On each day of testing, imipramine was dissolved in saline and injected into the rats at 2 ml/kg body weight.Control rats received an equivalent vehicle volume for the same treatment duration.The rats were individually forced to swim for 6 min in plastic cylinders (height 37 cm, diameter 15.5 cm), which contained water to a height of 20 cm, at 25°C. The total period of immobility during the 6-min testing period was recorded using the TAR-GET series/7 M analysis program (Neuroscience,Tokyo, Japan).Single administration of imipramine:Two swim sessions were conducted in an initial 13-min pretest;a 6-min test followed 24 h later. The duration of immobility was observed 30 min after the administration of saline(2 ml/kg, i.p.)or imipramine(1-10 mg/kg, i.p.).Chronic administration of imipramine:Saline(2 ml/kg, i.p.)or imipramine(1-10 mg/kg, i.p.)was given once daily to the rats for 14 days. On the 13th day, an initial 13-min pretest was performed before the administration of saline or imipramine. Following the ﬁnal treatment with saline or imipramine on Day 14, 30 min elapsed before immobility was observed.Single admin-istration of imipramine:Rats were forced to swim 6 min daily for 14 days. We chronically administered saline(2 ml/kg, i.p.)for 13 days. On Day 14, a single dose of saline or imipramine(10 mg/kg, i.p.)was administered.Immobility was observed 30 min after the administration.Chronic administration of imipramine:Rats were forced to swim for 6 min beginning 30 min after treatment with saline(2 ml/kg, i.p.)or imipramine(10 mg/kg, i.p.)once daily for 14 days. Immobility was observed 30 min after the ﬁnal administration of saline or imipramine on Day 14.Values are expressed as the means(±S.E.M.)of each group. The data were assessed using one-way analysis of variance(ANOVA), and the group means were compared using Dunnett’s test for multiple comparisons.Both the single and chronic administra-tion of imipramine(1-10 mg/kg, i.p.)potently decreased the duration of immobility in naı?ve rats (single:［F(3,39)＝7.81, P＜0.01］ (Fig. 1A);chronic:［F(3,28)＝7.72, P＜0.01］(Fig. 1B). We tested the eﬀects of imipramine on the duration of immobility in a chronic forced-swim stress test(Fig. 1 C). The chronic forced-swim stress for 14 days blocked the ability of a single administration of imipramine(10 mg/kg, i.p.) to decrease immobility. However, the chronic administra-tion of imipramine (10 mg/kg, i.p.) for 14 days signiﬁcantly shortened immobility following the 14-day repetition of chronic forced-swim stress［F(2,15)＝7.68,P＜0.01］(Fig. 1 C).Discussion In this study,we examined the inﬂuence of imipramine on the duration of immobility after chronic forced-swim stress testing. The chronic 14-day testing inhibited the ability of a single administration of imipramine(10 mg/kg,i.p.)to shorten immobility. However, the chronic admin-istration of imipramine (10 mg/kg, i.p.) for 14 days Kitamura et al. Acta Med. Okayama Vol. 58, No. 6 2722Acta Medica Okayama, Vol. 58 [2004], Iss. 6, Art. 3http://escholarship.lib.okayama-u.ac.jp/amo/vol58/iss6/3 shortened immobility in chronic forced-swim stress for 14 days. The chronic stress testing clearly inhibited imip-ramine’s immobility-shortening eﬀect, suggesting a link between the mechanism of drug action and the resulting behavioral changes.We previously reported that chronic, but not acute,forced-swim stress in rats increased frontal cortical 5-HT? receptor levels and the severity of the wet-dog shakes that they mediated［6］. Clinically, the up-regulation of 5-HT? receptors was reported in the platelets of depressed patients and in the frontal cortex of suicide victims［1-3］. Furthermore, it was reported that the number of 5-HT?receptors increases as a result of some types of chronic stress, such as forced running［9］and learned helplessness［10］. Therefore, this animal model of chronic forced-swim stress may shed light on the mechanism governing 5-HT? receptor up-regulation,which may be associated with the pathophysiology of depression.In rodents, the forced-swim test is widely used as a predictor of activity of antidepressant［7-8］. A single administration of antidepressants, including imipramine,screened in the forced-swim test, reduced the immobility of rodents in the forced-swim test. Although previous studies evaluated the eﬀects of antidepressants on im-mobility in the forced-swim test in naı?ve rats, few attempts have been made to examine their eﬀects on a model of chronic forced-swim stress testing. In this study, we demonstrated for the ﬁrst time that chronic forced-swim stress testing blocked the ability of a single administration of imipramine to shorten immobility. The precise mechanism underlying this inhibition remains unclear.Previously, we reported the eﬀects of adrenocor-ticotropic hormone (ACTH), which up-regulates the hypothalamic-pituitary-adrenal axis, on the immobilization of rats in the forced-swim test after the administration of imipramine［8］. Treatment with ACTH for 14 days blocked the shortening of immobility induced by either single or chronic administration of imipramine(10 mg/kg,i.p.)for 15 days. On the other hand, chronic ACTH treatment increased the wet-dog shakes induced by a 5-HT? receptor agonist, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane(DOI). The 14-day adminis-tration of imipramine did not inhibit the 14-day ACTH treatment from increasing DOI-induced wet-dog shakes.However, the chronic co-administration of imipramine and lithium decreased both the DOI-induced wet-dog Eﬀect of Imipramine on Stress December 2004 Fig.1  Eﬀects of single or 14-day chronic administration of imip-ramine on the duration of immobility during the forced-swim test in naı?ve rats and chronic forced-swim stress for 14 days in rats. (A)A single administration of imipramine(1-10 mg/kg, i.p.)was adminis-tered 30 min prior to testing. (B)Rats were administered imipramine(1-10 mg/kg, i.p.)once daily for 14 days. The ﬁnal administration of imipramine was given 30 min prior to testing. (C)Rats were forced to swim 6 min daily for 14 days. A single administration of imip-ramine(10 mg/kg, i.p.)was administered 30 min prior to the forced swim on Day 14 only. In the chronic administration of imipramine,rats were treated with imipramine(10 mg/kg, i.p.)once daily for 14 days. The ﬁnal administration of imipramine was given 30 min prior to testing. Values are expressed as the means±S.E.M. of 6-11 animals per group. Data were analyzed by one-way ANOVA, followed by Dunnett’s test. ?P＜0.05, ??P＜0.01 vs. control.2733Kitamura et al.: Influence of imipramine on the duration of immobility inProduced by The Berkeley Electronic Press, 2004 shakes and immobilization in forced-swim test rats treated with ACTH for 14 days［8, 11］. These ﬁndings suggest that inhibition of the 5-HT? receptor function may contribute to shortening the eﬀect of immobility in forced swim testing. In fact, we determined that the chronic,14-day administration of imipramine decreased the DOI-induced wet-dog shake response after chronic, 14-day forced-swim stress testing(data not shown). On the other hand, imipramine metabolizes to desipramine［12］.Desipramine is well known as a potent and selective inhibitor of noradrenaline reuptake. Porsolt et al.［9］suggested that desipramine shortened immobility more than did 2 selective serotonin reuptake inhibitors, citalo-pram and ﬂuoxetine. Therefore, the possibility that the noradrenergic system is involved in the eﬀects observed in the present study should not be ignored. Further studies are in progress to clarify the functions of the 5-HT?receptor and of the noradrenergic function in chronic forced-swim stress testing in rats.Clinically, it is well established that 2 to 3 weeks of treatment with antidepressants is necessary before the ﬁrst signs of therapeutic eﬃcacy appear. Likewise, the chronic administration of imipramine signiﬁcantly shor-tened immobility in the forced-swim test, even when administered concurrently with chronic forced-swim stress in this study. Furthermore, the immobility-shortening eﬀect of a single administration of imipramine was inhib-ited in chronic forced-swim-stressed rats. Therefore, the results suggested that chronic forced-swim-stressed rats may serve as an animal model for depressive conditions.References 1. Arango V, Ernsberger P, Marzuk PM, Chen J-S, Tierney H, Stanley M, Reis DJ and Mann JJ:Autoradiographic demonstration of in-creased serotonin 5-HT?andβ-adrenergic receptor binding sites in the brain of suicide victimus. Arch Gen Psychiatry(1990)47:1038-1047.2. Mann JJ, Stanley M, McBride PA and McEwen BC:Increased ser-otonin?andβ-adrenergic receptor binding in the frontal cortices of suicide victims. Arch Gen Psychiatry(1986)43:954-959.3. Pandey GN, Pandey SC, Janicak PG, Marks RC and Davis JM:Platelet serotonin-2 receptor binding sites in depression and sucide.Biol Psychiatry(1990)28:215-222.4. Banerjee SP, Kung LS, Riggi SJ and Chanda SK:Development of beta-adrenergic receptor subsensitivity by antidepressants. Nature(1977)268:455-456.5. Bergstrom DA and Kellar KJ:Adrenergic and serotonergic receptor binding in rat brain after chronic desmethylimipramine treatment. J Pharmacol Exp Ther(1979)209:256-261.6. Takao K, Nagatani T, Kitamura Y, Kawasaki K, Hayakawa H and Yamawaki S:Chronic forced swim stress of rats increases frontal cortical 5-HT?receptors and the wet-dog shakes they mediate, but not frontal corticalβ-adrenoceptors. Eur J Pharmacol(1995)294:721-726.7. Porsolt RD, Anton G, Blavet N and Jalfre M:Behavioural despair in rats:A new model sensitive to antidepressant treatments. Eur J Pharmacol(1978)47:379-391.8. Kitamura Y, Araki H and Gomita Y:Inﬂuence of ACTH on the eﬀects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test. Pharmacol Biochem Behav(2002)71:63-69.9. Mayeda AR, Simon JR, Hingtgen JN, Hofstetter JR and Aprison MH:Activity-wheel stress and serotonergic hypersensitivity in rats. Phar-macol Biochem Behav(1989)33:349-353.10. Martin JV, Edwards E, Johnson JO and Henn FA:Monoamine rece-ptors in an animal model of aﬀective disorder. J Neurochem(1990)55:1142-1148.11. Kitamura Y, Araki H, Suemaru K and Gomita Y:Eﬀects of imipramine and lithium on wet-dog shakes mediated by the 5-HT? receptor in ACTH-treated rats. Pharmacol Biochem Behav(2002)72:397-402.12. Nagy A:On the kinetics of imipramine and related antidepressants.Acta Psychiatr Scand Suppl(1980)280:147-156.Kitamura et al. Acta Med. Okayama Vol. 58, No. 6 2744Acta Medica Okayama, Vol. 58 [2004], Iss. 6, Art. 3http://escholarship.lib.okayama-u.ac.jp/amo/vol58/iss6/3

Influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats.

Okayama University Digital Information Repository

Influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats.

Abstract

Similar works

Full text

Available Versions

Okayama University Scientific Achievement Repository

Okayama University Digital Information Repository