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Neuroreport: Post Author Corrections: February 2, 2015 doi: 10.1097/WNR.0000000000000324 Animal behaviour, environmental influence: PDF Only
Immobility time during the forced swimming test predicts sensitivity to amitriptyline, whereas traveled distance in the circular corridor indicates resistance to treatment in female Wistar rats. Flores-Serrano, Ana G.; Zaldívar-Rae, Jaime; Salgado, Humberto; Pineda, Juan C.
Abstract Among the main issues in the pharmacological treatment of depression are the wide variation in response to antidepressants among individual patients and the lack of indexes that allow prediction of which drug will be effective in a particular case. We evaluated whether differential sensitivity to amitriptyline is related to dichotomous categorization of individuals on the basis of their behavioral responses to two common paradigms used to evaluate the potential of tricyclic drugs as antidepressants. Hence, we categorized a cohort of 38 female rats on the basis of their immobility time in the conditioning phase of the forced swimming test [FST; high immobility (HI) vs. low immobility (LI) rats] and their locomotor behavior in the circular corridor test [high locomotor response (HR) vs. low locomotor response (LR) rats]. We subjected the rodents to the FST while under the influence of vehicle (n=20) or amitriptyline (15 mg/kg; n=18). We found no statistical evidence of dependence between categorizations of rats on the basis of their behavior in the FST and circular corridor test. Rats categorized as HI/LI and HR/LR significantly differed in their sensitivity/resistance to amitriptyline, as evidenced by changes (or lack thereof) in their immobility time, climbing time, and swimming time during the FST. These results confirm that different behavioral styles among rats are linked to differential sensitivity/resistance to antidepressants. However, we specifically found that categorizing rats as HI/LI better reflected sensitivity to amitriptyline, whereas categorizing them as HR/LR better revealed resistance to the drug. These differential responses should be considered in experimental approaches. (C) 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Animal behaviour, environmental influence 1
Immobility time during the forced swimming test predicts sensitivity to amitriptyline, whereas traveled distance in the circular corridor indicates resistance to treatment in female Wistar rats Ana G. Flores-Serranoa, Jaime Zaldívar-Raeb, Humberto Salgadoa and Juan C. Pinedaa Among the main issues in the pharmacological treatment of depression are the wide variation in response to antidepressants among individual patients and the lack of indexes that allow prediction of which drug will be effective in a particular case. We evaluated whether differential sensitivity to amitriptyline is related to dichotomous categorization of individuals on the basis of their behavioral responses to two common paradigms used to evaluate the potential of tricyclic drugs as antidepressants. Hence, we categorized a cohort of 38 female rats on the basis of their immobility time in the conditioning phase of the forced swimming test [FST; high immobility (HI) vs. low immobility (LI) rats] and their locomotor behavior in the circular corridor test [high locomotor response (HR) vs. low locomotor response (LR) rats]. We subjected the rodents to the FST while under the influence of vehicle (n = 20) or amitriptyline (15 mg/kg; n = 18). We found no statistical evidence of dependence between categorizations of rats on the basis of their behavior in the FST and circular corridor test. Rats categorized as HI/LI and HR/LR significantly differed in their sensitivity/resistance to amitriptyline, as evidenced by changes (or lack thereof) in their immobility
Introduction Major depression is among the most frequent psychiatric disorders [1]. However, the efficacy of the available treatments for its control is still far from desirable levels [2]. The response to antidepressant treatments varies considerably among individual patients, and there are no indexes that allow prediction of which drug will be effective in a particular case [3]. The behavioral coping style or temperament of depressive patients seems to predict differences in both the evolution of their disease and their response to antidepressant treatment [4]. For instance, scores of the temperament dimension known as novelty-seeking are significantly lower in patients who did not respond to antidepressant treatment than in those who did [5,6]. This difference was specific for a component of the novelty-seeking dimension known as ‘exploratory excitability’ [7]. Consistent with these observations, it has been observed that the response of rodents to antidepressants in the forced swimming test (FST, an animal 0959-4965 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
time, climbing time, and swimming time during the FST. These results confirm that different behavioral styles among rats are linked to differential sensitivity/resistance to antidepressants. However, we specifically found that categorizing rats as HI/LI better reflected sensitivity to amitriptyline, whereas categorizing them as HR/LR better revealed resistance to the drug. These differential responses should be considered in experimental approaches. NeuroReport 00:000–000 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. NeuroReport 2015, 00:000–000 Keywords: amitriptyline, animal models, antidepressants, behavioral styles, circular corridor test, differential sensitivity/resistance to antidepressants, female, forced swimming test, Wistar rats a Department of Neurosciences, Autonomous University of Yucatán and bResearch Coordination, Anahuac Mayab University, Mérida, Yucatán, México
Correspondence to Juan C. Pineda, PhD, Department of Neurosciences, Autonomous University of Yucatan; 490 Itzaes Avenue, CP 97000, Mérida, Yucatán, México Tel: + 52 99 9924 6412; fax: + 52 99 9923 6120; e-mail:
[email protected] Received 19 November 2014 accepted 2 January 2015
model and protocol that tests the antidepressant activity of drugs) varies between animals expressing differences in exploratory excitability, as evidenced by their traveled distance in an open field or in a circular corridor [4,8]. In previous studies, it was also found that selective serotonin and norepinephrine reuptake inhibitors, such as citalopram, reboxetine, and the tricyclic antidepressant, amitriptyline, act differently on two kinds of female Wistar rats, classified as ‘high immobility time’ (HI) or ‘low immobility time’ (LI) rats on the basis of whether their immobility time (IT) during 5 min of the conditioning [9,10] or test [11] phase in the FST lay in the population’s lower third or upper third values. Increased swimming time (ST) and climbing time (CT) in the FST have been successfully used as indices of ‘antidepressantlike’ activity of candidate drugs, whereas IT is used as an index of ‘depressant-like’ activity [12]. Given the need for behavioral protocols to detect the differential sensitivities of individuals to antidepressants, in this work, we categorized a group of female Wistar rats DOI: 10.1097/WNR.0000000000000324
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2 NeuroReport 2015, Vol 00 No 00
on the basis of their locomotor responses in the circular corridor test, which also models their exploratory excitability and their tendency to immobilize in the FST. The FST is the most successful and commonly used behavioral protocol to test the potential antidepressant activity of drugs [12]. Amitriptyline has been shown to differentially modify the behavior of female Wistar rats in the FST [9]. Hence, we evaluated whether differential sensitivity to this tricyclic antidepressant is related to behavioral categorizations of rats and the nature of this potential relationship. Specifically, we asked whether female Wistar rats showing high and low locomotor responses to the circular corridor [labeled high-response (HR) and low-response (LR) rats [13]] also respectively show low immobility and high immobility [9] during the conditioning phase of the FST. We hypothesized that locomotor response, as measured in the circular corridor, is inversely linked to immobility, as measured in the FST, such that HR rats have LI and LR rats have HI. Thereafter, we predicted (i) significant dependence between being an HR/LR and an HI/LI rat with the previously described directionality, and (ii) a significantly lower IT score and higher CT and ST scores during the conditioning phase of the FST in HR rats compared with LR rats. We also sought possible differences in the behavior of HR and LR rats during the test phase of the FST after either vehicle or amitriptyline had been administered to the animals. As a significant correlation has been found between traveled distance and IT in male rats [13], we also explored whether IT or CT expressed by female rats in the FST was correlated with their traveled distance in the circular corridor.
Methods We used 38 female Wistar rats weighing between 215 and 230 g (2–3 months old), which were housed in groups of six and habituated to the laboratory environment for at least 1 week before testing with 12 : 12 h light/dark cycles (lights on at 07:00), an ambient temperature of 24 ± 1°C, and food and water supply ad libitum. All experiments were performed between 11:00 and 15:00 h. This study was approved by the Institutional Bioethics Committee of the CIR-UADY, and all efforts were made to minimize animal discomfort, according to the recommendations of the Guide for the Care and Use of Laboratory Animals [14]. Circular corridor test
The 38 rats were individually placed in a black acrylic circular corridor with external and internal diameters of 50 and 40 cm, respectively, and a height of 40 cm [15]. Radial white lines situated every 10 cm served as distance reference points. Locomotor activity of individual rats was monitored using a video camera and analyzed offline by counting the number of times a radial line was crossed (crossings score) during 30 min. To assign rats to the HR or LR category, we divided the 38 individual
crossings scores into tertiles. We thus classified rats in the upper tertile as HR rats and those in the lower tertile LR rats. The circular corridor was cleaned with a 70% ethanol solution and allowed to dry between tests. Forced swimming test
Rats were tested according to the modified FST procedure described by Detke et al. [16]. Seven days after the circular corridor test, each rat was placed in an acrylic cylinder (diameter = 20 cm, height = 50 cm) filled with water (kept at 25 ± 1°C) up to 30 cm from the base. Each animal was subjected to two behavioral observation sessions that were 24 h apart. Rats were housed individually between sessions, and the water in the tank was changed after each session. During the first session (conditioning phase), the naive animals remained in the water for 15 min, whereas during the second session (test phase) the animals were placed in the tank only for 5 min. Both observation sessions were videotaped for behavioral analyses. We reported the number of accumulated intervals of 5 s (bins) of the prevalent behavior during the initial 5 min of the first session, as well as for the entire duration of the second session (5 min), as described by Detke et al. [16]. We categorized the rats as HI or LI rats on the basis of whether they had an IT score in the upper tertile or the lower tertile of the entire set of subjects during the first 5 min of the conditioning phase of the test, respectively. Drugs
After the conditioning phase of the FST, 18 animals received three doses of amitriptyline hydrochloride over 24 h before the second session of the FST (Sigma, St. Louis, Missouri, USA; 15 mg/kg in 0.2 ml distilled water), and 20 rats received only vehicle by intraperitoneal injection 23, 4, and 1 h before the second observation session of the FST. This dose is in the mid range of the dose–effect relationship for IT on the FST [9]. Data analysis
Results are presented as mean ± 1 SEM or medians, as indicated. Independence of the variables was analyzed using Fisher’s exact test. After confirmation of normality and homoscedasticity, two-way analyses of variance were carried out, followed by Bonferroni’s tests, as indicated. These analyses were carried out and graphs were prepared using GraphPad Prism version 5 (GraphPad Software Inc., La Jolla, California, USA); we accepted results at a significance level of P less than 0.05.
Results Circular corridor tests and assignment to high-response and low-response categories
Crossings score distribution of the 38 rats tested did not significantly differ from a normal function (D’Agostino and Pearson omnibus and Shapiro–Wilks tests, P > 0.05). The mean crossings score was 161.3 ± 10 crossings and
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Behavior styles and antidepressant activity Flores-Serrano et al. 3
the median crossings score was 164 crossings. Rats in the upper tertile (HR subjects) had a mean crossings score of 234 ± 10 crossings (median 217 crossings; n = 12), whereas those in the lower tertile (LR subjects) had a mean crossings score of 95 ± 8 crossings (median = 96, n = 13). Of the rats, 13 fell within the middle tertile (not shown).
Forced swimming test, assignment to high-immobility versus low-immobility categories and relationship with responses in the circular corridor test
On the basis of the median IT score (36 bins) during the first 5 min of the conditioning phase of the FST, individuals in the upper tertile (HI subjects) had a mean IT of 45 ± 1 bins (median 44 bins, n = 13), whereas those in the lower tertile (LI subjects) had a mean IT of 28 ± 1 bins (median = 28 bins, n = 14). Of the rats, 11 fell within the middle tertile (not shown). Contrary to our expectations, there was no statistical evidence that being categorized as HR or LR and being assigned to the HI or LI groups were dependent variables (Fisher’s exact test, two-sided; P = 0.68, n = 23 HR/LR rats). This was further confirmed by the fact that the mean crossings scores of HI and LI rats that had also been categorized as either HR or LR (i.e. HI and LI rats that had fallen either within the lower or the upper tertile of crossings scores; 13 HI rats and 14 LI rats) did not significantly differ (t-test independent samples, t = 0.362, P > 0.05). This lack of a significant difference in the mean crossings scores persisted even when all HI and LI rats (n = 21 and n = 17, respectively) were compared, regardless of the crossings score tertile in which they had fallen (t-test independent samples, t = 0.330, P > 0.05). Thus, HI and LI rats did not differ in their locomotor response to the circular corridor.
Differential effects of amitriptyline on performance during the forced swimming test among highimmobility/low-immobility and high-response/lowresponse rats
Comparison of behavioral changes during the FST of HI and LI rats administered vehicle or amitriptyline evidenced differences in response to the drug among the two kinds of rats. As shown in Fig. 1A, HI rats administered vehicle showed a significant increase in IT (46 ± 1 to 55 ± 1 bins, P < 0.0001, n = 9) and a significant decrease in CT (12 ± 1 to 4 ± 1 bins, P < 0.0001, n = 9) between the conditioning and test phases of the FST. Conversely, HI rats administered amitriptyline showed a significant drop in IT (43 ± 1 to 29 ± 3 bins, P < 0.01, n = 4) and a significant increase in CT (11 ± 1 to 27 ± 4 bins, P < 0.01, n = 4) between the conditioning and test phases of the FST (Fig. 1A). HI rats showed no significant change in ST between the conditioning and test phases of the FST, regardless of whether they had received vehicle or amitriptyline (2 ± 1 and 1 ± 1 bins or 7 ± 1 and 4 ± 1 bins, respectively, P > 0.05; Fig. 1).
LI rats treated with vehicle showed no significant changes in IT (30 ± 1 and 38 ± 5 bins, P > 0.05, n = 7) and ST (7 ± 2 and 8 ± 4 bins, P > 0.05, n = 7) but showed a significant drop in CT (24 ± 2 and 15 ± 3 bins, P < 0.05, n = 7) between the two phases of the FST (Fig. 1B). LI rats treated with amitriptyline showed no significant change in IT (29 ± 2 and 25 ± 3 bins, P > 0.05, n = 7), but showed a significant increase in CT (22 ± 2 and 28 ± 3 bins, P < 0.05, n = 7; Fig. 1B) and ST (10 ± 1 to 6 ± 1 bins, P < 0.0001, n = 7). In other words, amitriptyline modulated IT and CT in HI rats but CT and ST in LI rats. LR and HR rats also responded differentially to amitriptyline, as evidenced in the FST. Among LR rats administered vehicle (Fig. 1C), IT did not significantly change (39 ± 3 and 43 ± 6 bins, P > 0.05, n = 7), CT significantly decreased (15 ± 3 to 9 ± 3 bins, P < 0.03, n = 7), and ST did not change (5 ± 1 and 7 ± 4 bins, P > 0.05, n = 7) between the two phases of the FST. LR rats that received amitriptyline showed no significant changes in either IT (39 ± 3 and 43 ± 6 bins, P > 0.05, n = 6), CT (15 ± 3 and 9 ± 3 bins, P < 0.05, n = 6), or ST (5 ± 1 and 7 ± 4 bins, P > 0.05, n = 6) from the observation to the test phases of the FST. Thus, LR rat behavior was qualitatively similar to that of LI rats when both rat types were under control conditions. However, the behavior of LR and LI rats under the effect of amitriptyline differed, with the former seemingly not responding to amitriptyline treatment. HR rats that received vehicle showed a significant increase in IT (42 ± 3 to 49 ± 4 bins, P < 0.01, n = 6), a significant decrease in CT (15 ± 2 to 8 ± 2 bins, P < 0.002, n = 6), and no change in ST (3 ± 1 and 3 ± 1 bins, P > 0.05, n = 6) between the two phases of the FST (Fig. 1D, right), whereas HR rats that received amitriptyline showed no change in IT (35 ± 2 and 30 ± 3 bins, P > 0.05, n = 6), a significant increase in CT (14 ± 3 to 23 ± 2 bins, P < 0.05, n = 6), and a significant reduction in ST (11 ± 2 to 7 ± 2 bins, P < 0.03, n = 6; Fig. 1D left). It can thus be stated that, qualitatively, the behavioral responses of HR and HI rats under control conditions showed similar change patterns along the FST. Meanwhile, HR and LI rats exhibited similar behavioral changes along the FST when treated with amitriptyline. Correlation between traveled distance and immobility time or climbing time in forced swimming test
Significant correlations between crossings scores and IT bins (positive; r2 = 0.69, P < 0.04, n = 7) or crossings scores and CT (negative; r2 = 0.68, P < 0.03) were found only in the test session of HR rats when the vehicle was applied.
Discussion Our results show that when rats were categorized as HI or LI rats on the basis of their IT in the FST, marked differences in sensitivity to amitriptyline among the two
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4 NeuroReport 2015, Vol 00 No 00
Fig. 1
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Amitriptyline (AMI) differentially modifies changes in behavior of high-immobility (HI) and low-immobility (LI), and low locomotor response (LR) and high locomotor response (HR) female Wistar rats between phases of the forced swimming test (FST). Scatterplots of (a) immobility time (IT), (b) climbing time (CT), and (c) swimming time (ST; measured as 5 s bins in 5-min trials) during the conditioning, C, and test, T, phases of the FST, among (A) HI rats, (B) LI rats, (C) LR rats, and (D) HR rats. AMI, rats receiving amitriptyline (1 mg/kg); Control, rats receiving vehicle. *P < 0.05, **P < 0.01, ***P < 0.001, paired t-tests.
groups emerged. In contrast, when the same group of rats was categorized as HR or LR rats according to the circular corridor test, the FST evidenced differences in resistance
to amitriptyline among these two categories. Therefore, proposed hypotheses were not supported by our results: (i) HI and LR rats exhibited different behavior and
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Behavior styles and antidepressant activity Flores-Serrano et al. 5
sensitivity to amitriptyline, whereas HI rats reciprocally changed IT and CT when they were tested with vehicle or amitriptyline; (ii) HR/LI rats that received vehicle or amitriptyline varied in CT and ST, without change in the IT, between the two sessions, whereas (iii) LR rats showed no change in behavior at all when they were under the influence of amitriptyline. Dependence between high-immobility/low-immobility and high-response/low-response categorizations
Fisher’s test did not provide support for our hypothesis that the same rats categorized as LI would be categorized as HR, whereas rats categorized as HI would be categorized as LR. This result was further confirmed by the lack of a significant difference in IT between rats in the HR and LR subgroups. Hence, the behavioral patterns of rats in the FST and the circular corridor test may be regarded as independent traits. However, both HI/LI and HR/LR groups differ in their behavior in the FST and in the influence that amitriptyline exerts on their behavior (see the Circular corridor tests and assignment to highresponse and low-response categories section). Differential sensitivity to amitriptyline
The performance of rats classified as HI or LI confirmed previous observations on the differential expressions of both the behavior during the FST of female Wistar rats and the sensitivity of these behaviors to amitriptyline in both rat subgroups [9,10]. It is known that norepinephrine and/or serotonin (5-HT) mediate the antidepressant effect of drugs [4]; however, there is no information on which of these systems is implicated in the putative relationship between drug activity and temperament. Our observations of a reduction in ST and IT in amitriptyline-treated LI or HI and HR rats, respectively, with an increase in CT in all the groups, may be explained by amitriptyline inhibiting the recapture of noradrenaline, as well as by many other putative mechanisms (e.g. effects on Na, Ca, and K channels, as well as Muscarinic and NMDA receptors; Fig. 1C and D) [17,18]. The mechanisms implicated in the putative relationship between locomotor response to novelty and antidepressant drug activity remain unknown. Hence, as a first step in understanding this relationship, we chose to use amitriptyline, as it is a drug whose antidepressant activity through blocking the reuptake of 5-HT and norepinephrine, as well as through other pathways, is well established. Comparable studies
HI rats spent more time walking and standing in the open field test than did rats categorized as LI [11]. Our HI rats also walked a longer distance in the circular corridor test compared with LI rats (see the Correlation between traveled distance and immobility time or climbing time in forced swimming test section). However, the authors did not explore the sensitivity of
HI or LI rats to antidepressants. In previous studies, Jama et al. [8] reported that the effects of desipramine differed among male HR and LR rats, whereas Taghzouti et al. [13] found that fluoxetine (20 mg/kg) reduced IT in LR rats but increased IT in HR rats. Interestingly, these authors reported a negative correlation between traveled distance in the circular corridor and IT in the FST for male rats, whereas in this study we found a positive correlation between these variables among HR female rats (see the Correlation between traveled distance and immobility time or climbing time in forced swimming test section). The fact that we could find such a significant correlation despite the small number of subjects in the HR subgroup (n = 7) and the opposite direction of the relationship in these studies emphasizes the relevance of considering sex-related differences in animal models of psychiatric disease and response to pharmacological treatment [19]. More recently, Hollis et al. [20] reported that HR rats consumed more sucrose solution than LR rats, but reduced intake after exposure to defeat; in contrast, in the sucrose intake in LR rats was unaffected by social defeat. It was also shown that, whereas HR rats are vulnerable to the induction of depression-like symptoms by social defeat stress, LR rats are not [21]. In our study, HR rats were sensitive to the stress of the FST, whereas LR rats were seemingly insensitive to it. In fact, this subgroup was also insensitive to amitriptyline (Fig. 1C and D). Conclusion
We identified subjects that are sensitive or resistant to a standard drug used to evaluate antidepressant activity. The intrinsic efficacy of these antidepressant treatments and the range of patients among whom these treatments are successful have not improved in decades. This may be due in part to the lack of understanding of the potential effects of individual responses to particular drugs.
Acknowledgements This work was financed by Conacyt CB2011-167436B; UADY CIRB-2011-0009 to J.C.P. CONACYT, CB-201101-168943 to H.S. Conflicts of interest
There are no conflicts of interest.
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