Depressive behavior induced by social isolation of predisposed female rats

Physiology & Behavior 151 (2015) 292–297

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Depressive behavior induced by social isolation of predisposed female rats☆ Patrícia Helena Zanier-Gomes a,⁎, Tomaz Eugênio de Abreu Silva b,1, Guilherme Cia Zanetti b, Évelyn Raquel Benati c,2, Nanci Mendes Pinheiro a, Beatriz Martins Tavares Murta a, Virgínia Oliveira Crema a a b c

Institute of Natural and Biological Sciences, Federal University of Triângulo Mineiro, Uberaba, MG, Brazil Medical School, Federal University of Triângulo Mineiro, Brazil Occupacional Therapy School, Federal University of Triângulo Mineiro, Brazil

H I G H L I G H T S • The forced swim test can predict predisposition to depressive behavior in rats. • Depressive behavior is evident when predisposed female rats are socially isolated. • Repeated administration of amitriptyline could treat the depressive behavior.

a r t i c l e

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Article history: Received 23 March 2015 Received in revised form 19 July 2015 Accepted 20 July 2015 Available online 21 July 2015 Keywords: Depressive behavior Rat Forced swim test

a b s t r a c t Depression is a mood disorder that is more prevalent in women and has been closely associated with chronic stress. Many models of depression have been suggested that consider different forms of stress. In fact, stress is present in the life of every human being, but only a few develop depression. Accordingly, it seems wrong to consider all stressed animals to be depressed, emphasizing the importance of predisposition for this mood disorder. Based on this finding, we evaluated a predisposition to depressive behavior of female rats on the forced swim test (FST), and the more immobile the animal was during the FST, the more predisposed to depression it was considered to be. Then, animals were subjected to the stress of social isolation for 21 days and were re-evaluated by the FST. The Predisposed/Isolated rats presented higher immobility times. Once all the rats had prior experience in the FST, we calculated an Index of Increase by Isolation, confirming the previous results. Based on this result, we considered the Predisposed/Isolated group as presenting depressive behavior (‘Depressed’) and the Nonpredisposed/Nonisolated group as the control group (‘Nondepressed’). The animals were distributed into 4 new groups: Nondepressed/Vehicle, Nondepressed/Amitriptyline, Depressed/Vehicle, Depressed/Amitriptyline. After 21 days of treatment, only the Depressed/Vehicle group differed from the other 3 groups, demonstrating the efficacy of amitriptyline in treating the depressive behavior of the Depressed animals, validating the model. This study shows that conducting an FST prior to any manipulation can predict predisposition to depressive behavior in female rats and that the social isolation of predisposed animals for 21 days is effective in inducing depressive behavior. This behavior can be considered real depressive behavior because it takes into account predisposition, chronic mild stress, and the prevalent gender. © 2015 Elsevier Inc. All rights reserved.

1. Introduction

☆ There are no conflicts of interest. This study was supported by Fundação de Ensino e Pesquisa de Uberaba (FUNEPU) (937/2010). We thank Roberto Frussa-Filho, in memoriam, for his academic assistance. ⁎ Corresponding author at: Praça Manoel Terra, 330, UFTM, Disciplina de Farmacologia, CEP 38025-015, Uberaba, MG, Brazil. E-mail address: [email protected] (P.H. Zanier-Gomes). 1 Medical School of ABC, São Paulo, SP, Brazil. 2 University of São Paulo, Bauru, SP, Brazil.

http://dx.doi.org/10.1016/j.physbeh.2015.07.026 0031-9384/© 2015 Elsevier Inc. All rights reserved.

Depression is a common mental disorder that is estimated to affect 350 million people worldwide [1]. A person presenting Major Depression Disorder (MDD) can develop depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, and reduced energy or concentration, according to the Diagnostic and Statistical Manual of Mental Disorders — DSM-V [2]. According to a large number of relevant studies, there is no ideal animal model of depression [3]. This difficulty may be due to its diagnosis,

P.H. Zanier-Gomes et al. / Physiology & Behavior 151 (2015) 292–297

which involves subjective evaluation without specific biochemical exams, or due to lack of knowledge about the disorder. MDD has been closely associated with stress [4,5]: enhancements of cortisol (in humans) or corticosterone (in rodents) seem to reduce hippocampal neurogenesis, while chronic, not acute, use of antidepressants increases neurogenesis and reduces cortisol/corticosterone [6]. Based on this finding, many models of depression have been suggested that consider different forms of stress, from acute or mild stress to chronic or severe stress. With respect to the human condition, mild stresses are more reliable, enhancing the validation of those animal models that use them over those that use severe stress. In this scenario, social isolation is a mild social stress that has been validated as a rodent animal model of depression [7,8]. The stress of modern life is a complaint for most of the global population, but despite its increasing occurrence, the global incidence of depression caused by the stress of modern life is only about 4.4% [9]. This highlights the importance of factors other than types of stress in the development of the disorder. An important factor is predisposition, which has been focused on the influence of genetic variation and environmental risk. The heritability of MDD is estimated to be only about 40% [10]. Based on this finding, the observations of Beck [11] related to the negative expectations for the future and society led us to a perceived behavioral predisposition; to extrapolate to rodents, prior to the application of any stress paradigm to induce depressive behavior, the animal's predisposition to depression should be considered. Finally, animal models of depression should ideally be based on a common etiology in both animals and humans [3]. Although depression is 1.5 to 3 times more prevalent in women [1,12], and some new animal models of MDD highlight this prevalence in animals [13–15], the majority of preclinical studies are conducted with males [16–18]. Based on predisposition, the higher prevalence in females and the use of mild stress to induce depressive behavior, this work aims to validate a feasible and reproducible model of depression that is more reliable in predicting the clinical condition (responding to repeated amitriptyline treatment for 21 days). 2. Methods 2.1. Animals For our experiment, 40 6-week-old female Wistar rats were used. They were housed in groups of 4 in standard polypropylene cages (32 × 40 × 18 cm), with free access to food and water. The room temperature was maintained at 24 ± 2 °C with a relative humidity of 50 ± 5% and a 12 h light/dark cycle. All procedures were carried out in accordance with NIH guidelines [19] and were approved by the Institutional Animal Care and Use Committee. 2.2. Social isolation The rats were chronically, mildly stressed by social isolation. The ‘Isolated’ animals were singly housed in standard polypropylene cages (32 × 40 × 18 cm) for 21 days under the same conditions described previously. 2.3. Forced swim test (FST) The forced swim test (FST) was used to predict the predisposition to depressive behavior during the Basal phase of the study and to assess their depressive behavior during the subsequent two phases of the study (Isolation and Treatment). The more immobile the animal was during the FST, the more depressed it was considered to be [20,21]. The rats were individually placed into glass cylinders measuring 50 cm high and 30 cm in diameter, which were filled with 30 cm of water at 24 ± 1 °C. Twenty-four hours after a single training session of 15 min, the animals were subjected to the FST test session (5 min in duration), which was repeated after isolation and treatment. The

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water was changed after each session, and the cylinder was cleaned. Following both sessions, the animals were dried with a towel and kept warm by a heating lamp for 15 min. All the tests were recorded for subsequent analysis and scored by the same observer, who was unaware of the group of each animal. A rat was considered immobile when it made only small movements to keep its head above water. 2.4. Drugs Because amitriptyline is an antidepressant with known efficacy in animal models at the dosage of 5 mg/kg [22,23] and obeys the need for repeated administration (21 days) for antidepressant efficacy [24], it was used to validate the model (as a positive control). Amitriptyline was diluted in a sterile saline solution (0.9% NaCl) and administered at a concentration of 5 mg/kg daily, via intraperitoneal injection (i.p.), for 21 days, at a final volume of 1 ml of solution per kilogram of weight. Control animals were injected with the same volume of a sterile saline solution i.p. daily for 21 days. 2.5. Statistics The data that assumed a parametric distribution were subjected to t test, or one-way ANOVA followed by Duncan's post hoc test. Those that were non-parametrically distributed were analyzed by the Kruskal– Wallis test followed by Dunnett's post hoc test. A probability of p b 0.05 was considered to demonstrate a significant difference for all of the comparisons made. 2.6. Procedures The procedures consisted of 3 phases: Basal, Isolation and Treatment. 2.6.1. Basal Previously, the rats were caged in groups of four and not handled for 2 weeks as an acclimatization period. Then, they were subjected to the FST for 15 min (training session). Twenty-four hours later, all the animals were evaluated by the FST — test session (5 min). The immobility presented during the test session was considered their “Basal” behavior and was used as a predictive measure for the predisposition to depressive behavior. The animals were classified by their immobility time, in increasing order. The 17 animals with shorter immobility times were considered to be not predisposed (‘Nonpredisposed’ group) to depressive behavior, and the 17 with longer immobility times were considered predisposed (‘Predisposed’ group) to depression (Fig. 1). For population density maintenance, the 6 animals with intermediate immobility time were excluded from future tests but were maintained in the box housing to maintain social interactions. Any new animal was introduced to a cage after the test, avoiding social stress. 2.6.2. Isolation The ‘Nonpredisposed’ and ‘Predisposed’ groups were divided into 2 groups: Isolated or Nonisolated, resulting in 4 groups: ‘Nonpredisposed/ Nonisolated’, ‘Nonpredisposed/Isolated’, ‘Predisposed/Nonisolated’ and ‘Predisposed/Isolated’. Both of the ‘Isolated’ groups were subjected to social isolation for 21 days. The ‘Nonisolated’ animals were kept in the same groups of four as before the Basal test. After the Isolation period (21 days), all of the animals were re-evaluated by the FST. 2.6.3. Treatment Based on the results of the Isolation period, only 2 groups were considered for the subsequent phase of the study (Treatment): ‘Nonpredisposed/Nonisolated’ and ‘Predisposed/Isolated’. For Treatment, the ‘Nonpredisposed/Nonisolated’ group was considered not depressed (‘Nondepressed’), while the ‘Predisposed/Isolated’ group was considered depressed (‘Depressed’). Those two groups were divided into two new groups, which were treated with amitriptyline or vehicle

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Fig. 1. Experimental design. FST: Forced swim test.

for 21 days, resulting in 4 groups: ‘Nondepressed/Vehicle’, ‘Nondepressed/Amitriptyline’, ‘Depressed/Vehicle’ and ‘Depressed/Amitriptyline’. During the Treatment period, all the animals were kept in the same social conditions as during the induction of depression (Isolation period): the animals of the Depressed groups remained isolated for 21 more days, and the animals of the Nondepressed groups remained in the same original cages of 4 animals. 3. Results We evaluated 40 female Wistar rats by the FST before any manipulation and measured their immobility times. A t test (predisposed × nonpredisposed) showed higher Basal levels of immobility in the Predisposed animals [t(18) = 6.12, p b 0.001]. A one-way ANOVA (for the future groups of four when the Isolated groups were not yet isolated) showed both predisposed groups to be higher, in terms of immobility, than the Nonpredisposed groups [F(3,30) = 25.17, p b 0.001] (see Fig. 2, basal bars). At this basal evaluation, the Predisposed/Isolated groups presented lower immobility than the Predisposed/Nonisolated groups, and both Predisposed groups differed from the Nonpredisposed ones.

Both groups (Predisposed and Nonpredisposed) were subjected to the mild stress of social isolation for 21 days. After the Isolation period, the four groups were resubjected to the FST. The Predisposed/Isolated animals presented higher immobility times [F(3,30) = 7.41, p b 0.001] (see Fig. 2, isolated bars). Isolation of the Nonpredisposed animals was not effective in achieving the same amount of increase in immobility. If only two groups were considered without the predisposition analysis and we performed a t test between the Isolated and Nonisolated groups, the effect of isolation appeared [t(32) = 2.72, p b 0.05], reflecting the vast majority of articles that are currently being published [25–27] in which the animals are only stressed, without considering their predisposition. According to the predisposition analyses made here, we could achieve a greater increase in immobility when predisposed animals were subjected to social isolation. Once all the rats had prior experience in the FST [28,29] during the Basal phase of the experiment and because it seems from Fig. 2 that all the rats of all the groups showed an increase in immobility during the second trial [after Isolation], we calculated an Index of Increase by Isolation by dividing the second immobility time by the first: After Isolation Immobility / Basal Immobility. The distribution was non-parametric. A Kruskal–Wallis test showed a difference between the groups [X(3) =

Fig. 2. FST after social isolation. The figure shows the FST immobility times of the four groups at the Basal test (gray bars) and after social isolation (striped bars). The bars represent the mean with standard error. One-way ANOVA followed by Duncan's post hoc test. *p b 0.05 compared to the Nonpredisposed groups at the Basal test (Nonpredisposed/Nonisolated and Nonpredisposed/Isolated); &p b 0.05 compared to the Nonpredisposed groups at the test after Isolation (Nonpredisposed/Nonisolated and Nonpredisposed/Isolated); op b 0.05 compared to the Predisposed/Nonisolated group at the test after Isolation.

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13.88, p b 0.005]. Fig. 3 shows the Increase by Isolation Index, presented as the mean ± standard error for a better comparison between groups, in addition to Fig. 2. Based on this result, we considered only the Predisposed/Isolated group as presenting depressive behavior (‘Depressed’) and the Nonpredisposed/Nonisolated group as the control group (‘Nondepressed’). The animals were distributed into 4 new groups: Nondepressed/Vehicle, Nondepressed/Amitriptyline, Depressed/Vehicle, and Depressed/Amitriptyline. After 21 days of treatment with amitriptyline or vehicle in all of the groups, one-way ANOVA followed by Duncan's post hoc test showed that the Depressed/Vehicle group differed from the other three groups [F(3,16) = 9.33, p b 0.01], demonstrating the efficacy of amitriptyline in treating the depressive behavior of the Depressed animals (Fig. 4). To discard prior experience or habituation to the FST [28,29], we calculated the Increase by Treatment Index by dividing the third immobility time by the second: After Treatment / After Isolation Immobility. The data were parametrically distributed, and ANOVA showed a difference between the groups [F(3,19) = 9.35, p b 0.005] — Fig. 5, confirming the previous results. 4. Discussion The relation between stress and depression has been described in a multitude of publications [13,27,30], and most of them have employed stressful manipulations such as inescapable shock [31], maternal separation [32], and predator presence or odor [33]. However, these intense stresses would be better models of post-traumatic stress [34] than depression. The most closely related stress to depression is mild but chronic [5,30,35], which we achieved by socially isolating rats for 21 to 42 days. In fact, stress is present in the life of every human being, but only a few develop depression [1]. Accordingly, it seems wrong to consider all stressed animals to be depressed. There are multifactorial factors that increase MDD predisposition, including genetic differences, but this phenotype can be demonstrated in a predisposition test, such as the basal FST, which should be considered prior to any stress paradigm. The majority of articles present animal models focused on one or more factors of recognized importance—such as chronic mild stress [13,30,36] and the susceptibility of strains such as Flinders Sensitive Line (FSL) [37, 38] and Wistar–Kyoto [39,40] rats or the female gender—but rarely have experiments that reported an animal model comprising susceptibility to depression associated with stress and gender, as was shown by our method (see Figs. 2 and 3). Emotion-related behavioral dysfunction can be induced in rodents by social isolation for three to four weeks [8,41]. Isolation stress significantly decreases the number of BrdUpositive cells in the dentate gyrus of isolated mice [42], demonstrating the impact of this stress on the hippocampus.

Fig. 3. Increase by Isolation (Index) — After Isolation FST Immobility / Basal FST Immobility. Bars represent the mean + standard error. Kruskal–Wallis followed by Dunnett's post hoc test. *p b 0.005 compared to the other groups (Nonpredisposed/Nonisolated, Nonpredisposed/Isolated and Predisposed/Nonisolated).

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We assessed the predisposition or the susceptibility of the animals to depressive behavior using the FST, and the same test was used to evaluate the effectiveness of both the induction of depressive behavior and the treatment. Prior experience with the FST [28,29] can allow the rat to keep afloat in the water without any effort to escape on a sequential test. To discard that effect, the results were confirmed by an index created between the two sequential trials. The rats were subjected to the FST three times: (1) Basal; (2) After Isolation; and (3) After Treatment. So, we had the Increase by Isolation Index (calculated by After Isolation Immobility / Basal Immobility) and the Increase by Treatment Index (calculated by After Treatment Immobility / After Isolation Immobility). Both indexes confirmed the results analyzed when considering only the immobility in the FST, showing that although an increase occurred in all the groups (due to the prior experience), the increase was significantly higher in the Predisposed/Isolated groups than in the Depressed/ Vehicle groups. The results show that it is possible to analyze predisposition to depressive behavior using the FST prior to any manipulation and demonstrate the fundamental importance of considering predisposition before a stress paradigm to induce depressive behavior because the Nonpredisposed animals subjected to Isolation had a lower increase in immobility, reproducing the clinical finding that although all of us experience stress, only those who are predisposed develop depression. After the Isolation period, if only two groups were considered without the predisposition analysis, a t test between the Isolated and Nonisolated groups showed the effectiveness of the isolation, reflecting the findings published in the vast majority of articles, in which the animals are stressed without considering their predisposition [4,6,8]. Comparisons between patients subjected to a period of stress and those not stressed would probably show a higher prevalence of depression in the stressed group. Conceptualizing an animal model of human depression is a difficult task because there is a lack of knowledge of the pathophysiology of the disorder and because depression involves a subjective diagnosis. In this way, depression differs from other pathologies, such as diabetes or hypertension, that have standardized diagnostic methods [5]. Although the FST was first described by Porsolt [21] as a depressioninducing test, it has been extensively used to assess [not induce] the depressive-like behavior of rodents [5,28,31,43]. The FST has gone through some changes [20], such as increases in the depth of the water [to ensure that no animal is able to touch the bottom] and the temperature of the water (to be warmer), which we used and described in the Methods section. The FST is also used as a screening test for antidepressants [44,45]. Other important tests can evaluate depression in rats, but they could be considered to assess different aspects of depression: Sucrose consumption or feeding latency is based on pleasure reduction, whereas FST considers helplessness. It is important to note that to be diagnosed as depressed (MDD) based on the DSM-V [2], a patient does not have to present both symptoms—anhedonia and depressed mood; thus, it is not reliable to expect both symptoms in an animal model. Although females are more susceptible to the development of affective disorders such as depression [46], preclinical stress research has focused mainly on male animals. Comparisons between neurogenesis assessments of both genders have shown that female Wistar rats isolated for three weeks present lower survival of dentate gyrus cells than those that were not isolated and not subjected to inescapable shock [47], emphasizing the relevance of both sex and stress in depression. Despite the importance of estrogen in the development of depression, hippocampal neurogenesis reduction [48], and mood disturbances related to the influence of different phases of the reproductive cycle in women [43], we did not take into account the estrous cycle of the animals. Chronic stress of female rats (for four weeks) can disrupt their estrous cycle [49]. Future experiments that take into account the different cycle phases could provide evidence of some differences. Different antidepressants are used for the treatment of depression, with great results, but all of them require two to four weeks of daily

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Fig. 4. FST after treatment. The figure shows the immobility time in the FST after treatment with amitriptyline or vehicle of the rats presenting (Depressed) or not presenting (Nondepressed) depressive behavior. The bars represent the mean with standard error. One-way ANOVA followed by Duncan's post hoc test. *p b 0.05 compared to the other groups (Nondepressed/Vehicle, Nondepressed/Amitriptyline and Depressed/Amitriptyline).

administration. Santarelli [24] demonstrated the importance of chronic treatment (21 days) to recover hippocampal neurogenesis and reduce depressive behavior in rodents. Our results showed the same efficacy of this treatment, and amitriptyline reduced the immobility time of depressed animals during the FST, validating the model. The current results show that conducting an FST prior to any manipulation can predict predisposition to depressive behavior in rats and that social isolation of predisposed female rats for 21 days is effective in inducing depressive behavior. This behavior can be considered real depressive behavior because it takes into account predisposition (genetic/epigenetic factors), chronic mild stress, and the prevalent gender.

5. Conclusions Although validated only for female Wistar rats, the results suggest that depressive behavior is induced when predisposed animals are socially isolated, as demonstrated by greater immobility during the FST. Repeated administration of amitriptyline was effective in treating the depressive behavior of the predisposed isolated rats. This validated model of depression resembles the human disorder: It comprises a predisposition and responds to chronic treatment. Future studies could apply this model to screen the efficacy of new drugs in studies of antidepressants in female Wistar rats.

Fig. 5. Increase by Treatment (Index) — After Treatment FST Immobility / After Isolation FST Immobility. The bars represent the mean + standard error. One-way ANOVA followed by Duncan post hoc test. *p b 0.005 compared to the other groups (Nondepressed/Vehicle, Nondepressed/Amitriptyline and Depressed/Amitriptyline).

References [1] M. Marina, Y.M. Taghi, M. van Ommeren, D. Chisholm, S. Saxena, World Health Organization. Depression: A Global Public Health Concern, Department of Mental Health and Substance Abuse, 2012. [2] D.J. Kupfer, D.A. Regier, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, Arlington, 2013. [3] C. Hendrie, A. Pickles, S.C. Stanford, E. Robinson, The failure of the antidepressant drug discovery process is systemic, J. Psychopharmacol. 27 (5) (May 2013) 407–413 discussion 13–6. PubMed PMID: 23222042. eng. [4] Y. Iguchi, S. Kosugi, H. Nishikawa, Z. Lin, Y. Minabe, S. Toda, Repeated exposure of adult rats to transient oxidative stress induces various long-lasting alterations in cognitive and behavioral functions, PLoS One 9 (12) (2014) e114024 PubMed PMID: 25489939. PMCID: PMC4260961. eng. [5] E.J. Nestler, M. Barrot, R.J. DiLeone, A.J. Eisch, S.J. Gold, L.M. Monteggia, Neurobiology of depression, Neuron 34 (1) (Mar 2002) 13–25 PubMed PMID: 11931738. eng. [6] P. Jiang, R.L. Dang, H.D. Li, L.H. Zhang, W.Y. Zhu, Y. Xue, et al., The impacts of swimming exercise on hippocampal expression of neurotrophic factors in rats exposed to chronic unpredictable mild stress, Evid. Based Complement. Alternat. Med. 2014 (2014) 729827 PubMed PMID: 25477997. PMCID: PMC4244932. eng. [7] M. Banasr, G.W. Valentine, X.Y. Li, S.L. Gourley, J.R. Taylor, R.S. Duman, Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat, Biol. Psychiatry 62 (5) (Sep 2007) 496–504 PubMed PMID: 17585885. eng. [8] Q.G. Ren, W.G. Gong, Y.J. Wang, Q.D. Zhou, Z.J. Zhang, Citalopram attenuates tau hyperphosphorylation and spatial memory deficit induced by social isolation rearing in middle-aged rats, J. Mol. Neurosci. 56 (1) (May 2015) 145–153 PubMed PMID: 25476250. eng. [9] A.J. Ferrari, F.J. Charlson, R.E. Norman, S.B. Patten, G. Freedman, C.J. Murray, et al., Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010, PLoS Med. 10 (11) (Nov 2013) e1001547 PubMed PMID: 24223526. PMCID: PMC3818162. eng. [10] E.M. Byrne, T. Carrillo-Roa, A.K. Henders, L. Bowdler, A.F. McRae, A.C. Heath, et al., Monozygotic twins affected with major depressive disorder have greater variance in methylation than their unaffected co-twin, Transl. Psychiatry 3 (2013) e269 PubMed PMID: 23756378. PMCID: PMC3693404. eng. [11] A.T. Beck, Cognitive Therapy and the Emotional Disorders, 1st ed. Plume, 1976. [12] M.A. Lopez Molina, K. Jansen, C. Drews, R. Pinheiro, R. Silva, L. Souza, Major depressive disorder symptoms in male and female young adults, Psychol. Health Med. 19 (2) (2014) 136–145 PubMed PMID: 23651450. eng. [13] A. Franceschelli, S. Herchick, C. Thelen, Z. Papadopoulou-Daifoti, P.M. Pitychoutis, Sex differences in the chronic mild stress model of depression, Behav. Pharmacol. 25 (5–6) (Sep 2014) 372–383 PubMed PMID: 25025701. eng. [14] M. Llorens-Martín, J.L. Trejo, Mifepristone prevents stress-induced apoptosis in newborn neurons and increases AMPA receptor expression in the dentate gyrus of C57/BL6 mice, PLoS One 6 (11) (2011) e28376 PubMed PMID: 22140582. PMCID: PMC3227665. eng. [15] S.C. Stanley, S.D. Brooks, J.T. Butcher, A.C. d'Audiffret, S.J. Frisbee, J.C. Frisbee, Protective effect of sex on chronic stress- and depressive behavior-induced vascular dysfunction in BALB/cJ mice, J. Appl. Physiol. (1985) 117 (9) (Nov 2014) 959–970 PubMed PMID: 25123201. PMCID: PMC4217050. eng. [16] W. Ang, G. Chen, L. Xiong, Y. Chang, W. Pi, Y. Liu, et al., Synthesis and biological evaluation of novel naphthalene compounds as potential antidepressant agents, Eur. J. Med. Chem. 82 (Jul 2014) 263–273 PubMed PMID: 24915002. eng. [17] A. Lockridge, B. Newland, S. Printen, G.E. Romero, L.L. Yuan, Head movement: a novel serotonin-sensitive behavioral endpoint for tail suspension test analysis, Behav. Brain Res. 246 (Jun 2013) 168–178 PubMed PMID: 23499706. eng.

P.H. Zanier-Gomes et al. / Physiology & Behavior 151 (2015) 292–297 [18] Y.C. Tse, I. Montoya, A.S. Wong, A. Mathieu, J. Lissemore, D.C. Lagace, et al., A longitudinal study of stress-induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat, Hippocampus 24 (9) (Sep 2014) 1120–1128 PubMed PMID: 24753271. eng. [19] K. Bayne, Revised Guide for the Care and Use of Laboratory Animals available. American Physiological Society, Physiologist 39 (4) (Aug 1996) 199, 208–199, 11 PubMed PMID: 8854724. eng. [20] J.F. Cryan, R.J. Valentino, I. Lucki, Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test, Neurosci. Biobehav. Rev. 29 (4–5) (2005) 547–569 PubMed PMID: 15893822. eng. [21] R.D. Porsolt, G. Anton, N. Blavet, M. Jalfre, Behavioural despair in rats: a new model sensitive to antidepressant treatments, Eur. J. Pharmacol. 47 (4) (1978 Feb) 379–391 PubMed PMID: 204499. eng. [22] E.M. Cotella, I.M. Lascano, G.M. Levin, M.M. Suarez, Amitriptyline treatment under chronic stress conditions: effect on circulating catecholamines and anxiety in early maternally separated rats, Int. J. Neurosci. 119 (5) (2009) 664–680 PubMed PMID: 19283592. eng. [23] K.L. Paumier, C.E. Sortwell, L. Madhavan, B. Terpstra, B.F. Daley, T.J. Collier, Tricyclic antidepressant treatment evokes regional changes in neurotrophic factors over time within the intact and degenerating nigrostriatal system, Exp. Neurol. 266 (2015 Apr) 11–21 PubMed PMID: 25681575. PMCID: PMC4382385. eng. [24] L. Santarelli, M. Saxe, C. Gross, A. Surget, F. Battaglia, S. Dulawa, et al., Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science 301 (5634) (2003 Aug) 805–809 PubMed PMID: 12907793. eng. [25] J. Lu, X.Y. Wu, Q.B. Zhu, J. Li, L.G. Shi, J.L. Wu, et al., Sex differences in the stress response in SD rats, Behav. Brain Res. 284 (2015 May) 231–237 PubMed PMID: 25687843. eng. [26] M.M. Wilkin, P. Waters, C.M. McCormick, J.L. Menard, Intermittent physical stress during early- and mid-adolescence differentially alters rats' anxiety- and depression-like behaviors in adulthood, Behav. Neurosci. 126 (2) (2012 Apr) 344–360 PubMed PMID: 22352791. eng. [27] L. Ge, M.M. Zhu, J.Y. Yang, F. Wang, R. Zhang, J.H. Zhang, et al., Differential proteomic analysis of the anti-depressive effects of oleamide in a rat chronic mild stress model of depression, Pharmacol. Biochem. Behav. 131 (2015 Apr) 77–86 PubMed PMID: 25641667. eng. [28] J. Su, N. Hato-Yamada, H. Araki, H. Yoshimura, Test–retest paradigm of the forced swimming test in female mice is not valid for predicting antidepressant-like activity: participation of acetylcholine and sigma-1 receptors, J. Pharmacol. Sci. 123 (3) (2013) 246–255 PubMed PMID: 24162025. eng. [29] L.T. Yi, J. Li, Q. Liu, D. Geng, Y.F. Zhou, X.Q. Ke, et al., Antidepressant-like effect of oleanolic acid in mice exposed to the repeated forced swimming test, J. Psychopharmacol. 27 (5) (2013 May) 459–468 PubMed PMID: 23151611. eng. [30] P. Willner, The validity of animal models of depression, Psychopharmacology 83 (1) (1984) 1–16 PubMed PMID: 6429692. eng. [31] R.C. Drugan, J.P. Christianson, T.A. Warner, S. Kent, Resilience in shock and swim stress models of depression, Front. Behav. Neurosci. 7 (2013) 14 PubMed PMID: 23450843. PMCID: PMC3584259. eng. [32] M.B. Hennessy, N.P. Stafford, B. Yusko-Osborne, P.A. Schiml, E.D. Xanthos, T. Deak, Naproxen attenuates sensitization of depressive-like behavior and fever during maternal separation, Physiol. Behav. 139 (2015 Feb) 34–40 PubMed PMID: 25449392. PMCID: PMC4275325. eng. [33] L.J. Chen, B.Q. Shen, D.D. Liu, S.T. Li, The effects of early-life predator stress on anxiety- and depression-like behaviors of adult rats, Neural Plast. 2014 (2014) 163908 PubMed PMID: 24839560. PMCID: PMC4009288. eng.

297

[34] S.T. Manion, T.H. Figueiredo, V. Aroniadou-Anderjaska, M.F. Braga, Electroconvulsive shocks exacerbate the heightened acoustic startle response in stressed rats, Behav. Neurosci. 124 (1) (2010 Feb) 170–174 PubMed PMID: 20141293. eng. [35] L. Zheng, X. Zheng, Integration of animal behaviors under stresses with different time courses, Neural Regen. Res. 9 (15) (2014 Aug) 1464–1473 PubMed PMID: 25317159. PMCID: PMC4192949. eng. [36] R.J. Katz, K.A. Roth, B.J. Carroll, Acute and chronic stress effects on open field activity in the rat: implications for a model of depression, Neurosci. Biobehav. Rev. 5 (2) (1981) 247–251 PubMed PMID: 7196554. eng. [37] D.H. Overstreet, E. Friedman, A.A. Mathé, G. Yadid, The Flinders Sensitive Line rat: a selectively bred putative animal model of depression, Neurosci. Biobehav. Rev. 29 (4–5) (2005) 739–759 PubMed PMID: 15925699. eng. [38] D. Schijven, V.C. Sousa, J. Roelofs, B. Olivier, J.D. Olivier, Serotonin 1A receptors and sexual behavior in a genetic model of depression, Pharmacol. Biochem. Behav. 121 (2014 Jun) 82–87 PubMed PMID: 24345571. eng. [39] B. Getachew, S.R. Hauser, R.E. Taylor, Y. Tizabi, Desipramine blocks alcohol-induced anxiety- and depressive-like behaviors in two rat strains, Pharmacol. Biochem. Behav. 91 (1) (2008 Nov) 97–103 PubMed PMID: 18640149. PMCID: PMC3197815. eng. [40] L.L. Hurley, L. Akinfiresoye, O. Kalejaiye, Y. Tizabi, Antidepressant effects of resveratrol in an animal model of depression, Behav. Brain Res. 268 (2014 Jul) 1–7 PubMed PMID: 24717328. PMCID: PMC4033784. eng. [41] G. Pinna, E. Costa, A. Guidotti, SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake, Curr. Opin. Pharmacol. 9 (1) (2009 Feb) 24–30 PubMed PMID: 19157982. PMCID: PMC2670606. eng. [42] H. Dong, B. Goico, M. Martin, C.A. Csernansky, A. Bertchume, J.G. Csernansky, Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress, Neuroscience 127 (3) (2004) 601–609 PubMed PMID: 15283960. eng. [43] D'Aquila PS, Canu S, Sardella M, Spanu C, Serra G, Franconi F. Dopamine is involved in the antidepressant-like effect of allopregnanolone in the forced swimming test in female rats. Behav. Pharmacol. 2010 Feb;21(1):21–8. PubMed PMID: 20009921. eng. [44] M. Bianchi, E.E. Baulieu, 3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders, Proc. Natl. Acad. Sci. U. S. A. 109 (5) (2012 Jan) 1713–1718 PubMed PMID: 22307636. PMCID: PMC3277154. eng. [45] H. Zhang, W. Tückmantel, J.B. Eaton, P.W. Yuen, L.F. Yu, K.M. Bajjuri, et al., Chemistry and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile, J. Med. Chem. 55 (2) (2012 Jan) 717–724 PubMed PMID: 22171543. PMCID: PMC3292870. eng. [46] V. Mourlon, A. Baudin, O. Blanc, A. Lauber, B. Giros, L. Naudon, et al., Maternal deprivation induces depressive-like behaviours only in female rats, Behav. Brain Res. 213 (2) (2010 Dec) 278–287 PubMed PMID: 20488211. eng. [47] C. Westenbroek, J.A. Den Boer, M. Veenhuis, G.J. Ter Horst, Chronic stress and social housing differentially affect neurogenesis in male and female rats, Brain Res. Bull. 64 (4) (2004 Dec) 303–308 PubMed PMID: 15561464. eng. [48] J.C. Pruessner, K. Dedovic, M. Pruessner, C. Lord, C. Buss, L. Collins, et al., Stress regulation in the central nervous system: evidence from structural and functional neuroimaging studies in human populations — 2008 Curt Richter Award Winner, Psychoneuroendocrinology 35 (1) (2010 Jan) 179–191 PubMed PMID: 19362426. eng. [49] C.J. Herzog, B. Czéh, S. Corbach, W. Wuttke, O. Schulte-Herbrüggen, R. Hellweg, et al., Chronic social instability stress in female rats: a potential animal model for female depression, Neuroscience 159 (3) (2009 Mar) 982–992 PubMed PMID: 19356682. eng.