Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant Impairment of Social Behaviors Induced by Social Defeat Stress Exposure as Juveniles

Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant... Background: Extensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles. Methods: Juvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1  day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15  days. Social behaviors were assessed at 1 and 15  days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress. Results: Stress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects. Conclusions: These findings suggest that social defeat stress exposure as juveniles induces the treatment-resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress- related psychiatric disorders in adolescents with adverse juvenile experiences. Keywords: social defeat stress, juvenile, adolescent, social behaviors, monoaminergic neuronal system Received: January 5, 2018; Revised: March 20, 2018; Accepted: March 28, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 837 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 838 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Monoaminergic neuronal systems have attracted the attention of researchers with regard to the impairment of social behaviors induced by social defeat stress exposure as adults. However, the importance of monoaminergic neuronal systems in the impair - ment of social behaviors induced by exposure to social defeat stress as juveniles remains poorly understood; thus, in the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles. Exposure to social defeat stress as juveniles leads to the treatment-resistant impairment of social behaviors in adolescents, because of dysfunction of the serotonergic and dopaminergic neuronal systems. Repeated administration of a combination of sertraline and aripiprazole showed additive effects in attenuating this impairment of social behaviors. This may be useful as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adoles- cents with adverse juvenile experiences. Introduction Adverse juvenile experiences, including physical or sexual the role of monoaminergic neuronal systems in the impairment violence and neglect, often induce adverse mental health out- of social behaviors induced by social defeat stress exposure as comes later in life (Afifi, 2011; Annerback et al., 2012; McKenzie juveniles remains unclear. and Scott, 2012). Epidemiological studies have demonstrated The present study was designed to investigate the role of that adverse juvenile experiences increase the risk for stress- monoaminergic neuronal systems in the impairment of social related psychiatric disorders, particularly major depressive dis- behaviors induced by social defeat stress exposure as juveniles. order (MDD), anxiety disorder, and posttraumatic stress disorder We determined the functional and neurochemical changes in (Weber et  al., 2008; Weich et  al., 2009; McLaughlin et  al., 2010). the monoaminergic neuronal systems of mice exposed to social These psychiatric disorders induced by adverse juvenile experi- defeat stress as juveniles using biochemical techniques. We also ences frequently involve marked dysfunction in social activity investigated the effect of antidepressants and aripiprazole on during adolescence and adulthood (Sandi and Haller, 2015). the impairment of social behaviors in adolescent mice exposed The monoaminergic neuronal system has attracted increas- to social defeat stress as juveniles. ing attention of researchers in the field of stress-related psychi- atric disorders (Flugge, 2000 Pitteng ; er and Duman, 2008; Krystal Materials and Methods and Neumeister, 2009). Polymorphism of the serotonin (5-HT) transporter (5-HTTLPR genotype) has been reported to be a sus- Animals ceptibility factor for posttraumatic stress disorder in the inter - action between adult traumatic events and childhood adversity Male C57BL/6J and ICR mice were obtained from Japan SLC, Inc. (Steckler and Risbrough, 2012). Further, monoaminergic neu- Juvenile, male C57BL/6J mice (3 weeks old) were used to expo- ronal dysregulation may contribute vulnerability to stress as a sure to social defeat stress. Aggressive, male ICR mice (over 7 factor in the development of anxiety disorders, because 5-HT weeks old) for social defeat stress were screened based on the reuptake inhibitors and dual 5-HT/noradrenaline (NA) reuptake duration of attacks on C57BL/6J mice, with more than 1/10 min- inhibitors are effective in treating anxiety disorders (Morilak utes as the inclusion criterion. Unfamiliar target male ICR mice and Frazer, 2004). Low CSF levels of 5-hydroxyindoleacetic acid (over 4–6 weeks old) were used for the social interaction test. (5-HIAA), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), They were housed in plastic cages in a regulated environment and homovanilic acid (HVA) have been hypothesized to be (23°C ± 1°C, 50 ± 5% humidity), with a 12-hour-light/-dark cycle involved in MDD, although the published literature is contra- (lights on at 9:00 am). Food (CE2; Clea Japan Inc.) and tap water dictory (Placidi et al., 2001). Extensive investigation on the role were available ad libitum. All experiments were conducted in of monoaminergic neuronal systems has also been performed accordance with the Guidelines for Animal Experiments of the in rodents exposed to social defeat stress as adults (Krishnan Nagoya University Graduate School of Medicine. Procedures et al., 2007; Cao et al., 2010; Chen et al., 2012; Boyarskikh et al., involving animals and their care were conformed to the 2013). international guidelines set out in the National Institutes of Mice exposed to social defeat stress as adults display the Health’s Guide for the Care and Use of Laboratory Animals (NIH impairment of social behaviors (Berton et  al., 2006; Tsankova Publications No. 8023, revised 1978). et  al., 2006). Previous studies have shown that tryptophan hydroxylase 2 knockin mice, which show 60% to 80% reduc- Drug Administration tion in brain 5-HT, have increased susceptibility to social defeat Desipramine hydrochloride, sertraline hydrochloride, and ari- stress (Nakayama et al., 2003). The impairment of social behav- iors induced by social defeat stress exposure is dependent on piprazole were purchased from Sigma-Aldrich, Tokyo Chemical Industry Co, Ltd, and Wako Pure Chemical Industries, Ltd, the mesolimbic dopamine (DA) circuit (Tanaka et  al., 2012). In addition, NA transporter-knockout mice resist the impairment respectively. Desipramine and sertraline were dissolved in dis- tilled water. Aripiprazole was dissolved in 100% acetic acid and of social behaviors induced by social defeat stress exposure (Haenisch et  al., 2009). These findings suggest that brain mon- diluted with distilled water. From 1  day after the last social defeat stress exposure, i.p. oaminergic neuronal systems are involved in the impairment of social behaviors induced by social defeat stress exposure. administration of 10 and 20  mg/kg desipramine, 5 and 10  mg/ kg sertraline, or 0.003 and 0.01  mg/kg aripiprazole was com- We previously found that juvenile mice were more vulnerable to the impairment of social behaviors induced by social defeat menced; this treatment was performed once a day for 15 days. The administration volume was 10 mL/kg per mouse. stress exposure than adult mice (Mouri et  al., 2018). However, Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 839 ice-cold plate according to the atlas (Paxinos and Franklin, 2004). Social Defeat Stress Each tissue sample was quickly frozen on dry ice, weighed, and Social defeat stress exposure was carried out according to stored in a deep freezer at -80°C until assay. the method outlined in previous reports (Berton et  al., 2006; Krishnan et  al., 2007) with minor modifications. Prior to social Determination of Monoamines and Their defeat stress, an aggressive ICR mouse was habituated to social Metabolites defeat stress cages for 10 minutes. C57BL/6J mice (3 weeks old) were exposed to a different aggressive ICR mouse for 10 minutes The concentrations of monoamines and their metabolites were each day for 10 consecutive days. The pairing of defeated and determined using a high-performance liquid chromatography aggressive mice was randomized daily to minimize the effects system with an electrochemical detector (Eicom) as described in of variability in aggression that the mice were exposed to. previous reports (Noda et al., 1997, 1998). Briefly, each frozen tis- Defeat was defined as the display of defensive behaviors by sue sample was homogenized with an ultrasonic processor (475 C57BL/6J mice, such as escape and submissive postures during W, Model XL2020, Heat Systems Inc.) in 350 μL of 0.2 M perchloric physical attacks by an aggressive mouse. Submissive posture acid containing isoproterenol (internal standard). The homoge- was defined as standing upright with the belly exposed to the nate was placed in ice for 30 minutes and then centrifuged at aggressor. The duration of defensive behaviors was recorded 20 000 × g for 15 minutes at 0°C. The supernatant was mixed with according to our previous report (Mouri et  al., 2018). After 10 1 M sodium acetate to adjust the pH to 3.0 and then injected minutes, an aggressive mouse was separated from the defeated into a liquid chromatography system equipped with a reversed- mouse to avoid habituation to the defeated mouse and placed in phase ODS-column (3 × 150  mm, diameter of stationary phase its group-housed home cage for the next 24 hours. grains 5 μm: Eicompak SC-5ODS, Eicom) and an electrochemi- We previously found that mice exposed to a nonaggressive cal detector (model ECD-700, Eicom). The column temperature ICR mouse (undefeated mice) as well as an empty cage (control was maintained at 25°C, and the detector potential was set at mice) for 10 consecutive days showed significantly increased +750 mV. The mobile phase consists of 0.1 M citric acid and 0.1 duration at the interaction zone in the second session com- M sodium acetate, pH 3.5, containing 15% methanol, 220  mg/L pared with that in the first session (Mouri et al., 2018). Thus, it sodium-l-octanesulfonate, and 5  mg/L ethylenediaminetet- is unlikely that defeated mice were habituated to expose ICR raacetic acid; the flow rate was 0.5 mL/min. Data were collected mouse during social defeat stress and did not approach familiar and analyzed with the PowerChrom v2.6.4 software (eDAQ). target ICR mouse. Control mice were exposed to an empty cage as described in Statistical Analysis our previous report (Mouri et al., 2018). All results are expressed as the mean± SEM for each group. Statistical significance was determined using 1-way or 2-way Social Interaction Test ANOVA followed by Bonferroni’s test. The Student’s t test was used to compare 2 sets of data. P <.05 w as taken to indicate sig- The adolescent mice (4 or 6 weeks old) were subjected to the nificance. Data were analyzed with SPSS 24 software (IBM). social interaction test at 1 and 15 days after the last stress expo- sure. The social interaction test was performed from 10:00 am to 5:00 pm in a sound-attenuated room, as described in our pre- Results vious report (Mouri et al., 2018). The apparatus consisted of an open gray nonreflecting acrylic box (W42 × D42 × H30 cm) and the The Impairment of Social Behaviors in Adolescent transparent Plexiglas enclosure (W10 × D6.5 × H30  cm) with 30 Mice Exposed to Social Defeat Stress as Juveniles holes (10 mm in diameter). A lightbulb (54 W), not directly seen by the mouse, was attached to the upper part of the apparatus Adolescent, male C57BL/6J mice were exposed to social defeat and provided constant illumination of approximately 20 lux. stress as juveniles for 10 consecutive days. When juvenile The social interaction test consisted of 2 sessions: in the first mice body weight was measured immediately after the stress session, the mouse was allowed to freely explore and habitu- exposure of 10 consecutive days, the stress exposure did not ate to the test environment for 30 minutes in the absence of affect body weight gain (data not shown), in consistent with an unfamiliar target ICR mouse, in consistent with a previous a previous report (Mouri et  al., 2018). One day after the last report (Mouri et  al., 2018). This was done to reduce the time stress exposure, mice were subjected to the social interac- spent in the interaction zone by exploring the apparatus itself tion test. In the first session without an unfamiliar ICR mouse, during the second session. The second session commenced 1 there was no significant difference between groups in the minute after the first session, and the mouse was returned to time spent in the interaction zone and engaging in explora- the apparatus for 5 minutes in the presence of an unfamiliar tory activity within the apparatus (Figure  1A). In the second target ICR mouse. During the test, the time spent in the interac- session, control mice approached the unfamiliar target ICR tion zone (6 cm width) was recorded for the last 5 minutes of the mouse and showed significantly increased time spent in the first (target absent) and for the 5 minutes of the second (target interaction zone than in the first session (Figure 1A). However, present) sessions, using a video-tracking system (EthoVision XT; in the second session, the mice exposed to the stress as juve- Noldus Information Technology). niles for 10 consecutive days spent significantly less time in the interaction zone than the control group, although there were no difference in exploratory activity between control and Preparation of Brain Samples defeated groups (Figure 1A). When tested 15  days after the last stress exposure, mice Each mouse was killed immediately before or soon after the social interaction test. Their brains were rapidly removed and exposed to the stress as juveniles still spent less time in the interaction zone in the second session, although there was no the prefrontal cortex (PFC), nucleus accumbens (NAc), hip- pocampus (HIP), and amygdala (AMG) were dissected out on an difference in exploratory activity between control and defeated Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 840 | International Journal of Neuropsychopharmacology, 2018 groups (Figure  1B). There was also no significant difference group (Figure  2A). In the PFC, NAc, and AMG, there was a sig- between groups in the time spent in the interaction zone and nificant decrease in the 5-HIAA/5-HT ratio in the tested defeated engaging in exploratory activity within the apparatus in the group compared with that in tested control group (Figure  2A). first session (Figure 1B). These results indicate that social defeat There were no significant changes in the 5-HIAA/5-HT ratio in stress exposure as juveniles induces the persistent impairment the HIP when all groups were compared (Figure 2A). No changes of social behaviors in adolescents. in the (DOPAC + HVA)/DA ratio (DA metabolism) were observed in the tested control group (Figure 2B), whereas the ratio in the NAc, HIP, and AMG was significantly decreased in the both non- Changes in Monoamine Metabolisms in Brain tested and tested defeated groups compared with that in the cor - Regions of Adolescent Mice Exposed to Social Defeat responding control groups, respectively (Figure  2B). There were Stress as Juveniles no significant changes in the MHPG/NA ratio (NA metabolism) in To examine the influence of social defeat stress exposure as the all brain regions when all groups were compared (Figure 2C). juveniles on monoaminergic neuronal systems, we measured Significant changes in the concentrations of monoamines the concentrations of monoamines and their metabolites in the and their metabolites were observed as follows:  the 5-HIAA PFC, NAc, HIP, and AMG immediately before (nontested group) or concentration in the PFC, NAc, and AMG was significantly after (tested group) the social interaction test (Tabl ). The e 1 ratios increased in the tested control group compared with that in the of 5-HIAA/5-HT, [3, 4-dihydroxyphenyl acetic acid (DOPAC) + nontested control group. The increase in 5-HIAA concentration HVA]/DA, and MHPG/NA, which are used as indices of the 5-HT, in the PFC, NAc, and AMG was significantly decreased in the DA, and NA turnover rates, were calculated in the PFC, NAc, HIP, tested defeated group compared with the tested control group. and AMG of the nontested and tested groups (Figure 2). The 5-HT concentration in the PFC was significantly increased A significant increase in the 5-HIAA/5-HT ratio (5-HT metab- in the tested defeated group compared with that in the tested olism) was observed in the PFC and AMG of the tested con- control group. The HVA concentration in the NAc was signifi- trol group compared with that of the nontested control group cantly increased in the tested control group compared with (Figure  2A). Such significant increase in the 5-HIAA/5-HT ratio that in the nontested control group. The DA and DOPAC con- was not observed in the PFC and AMG of the tested defeated centrations in the HIP and NAc were significantly increased and Figure 1. The impairment of social behaviors in adolescent mice exposed to social defeat stress as juveniles. (A) Duration at interaction zone (left) and exploratory activity (right) 1 day after the last stress exposure. (B) Duration at interaction zone (left) and exploratory activity (right) 15 days after the last stress exposure. Each col- umn represents the mean ± SEM (n = 12–15). Two-way ANOVA: duration at interaction zone: (A) F (1, 25) = 2.10, P = .16; F (1, 25) = 1.08, P = .31; F (1, 25) = 13.7, defeat session defeat × session P < .01. (B) F (1, 25) = 7.16, P = .13; F (1, 25) = 0.57, P = .46; F (1, 25) = 22.3, P < .01. **P < .01 vs corresponding control in the first session (Student’s t test). ##P < .01 defeat session defeat × session vs control group (Student’s t test). Control: mice exposed to an empty cage, defeated: mice exposed to an aggressive ICR mouse. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 841 Table 1. Changes in Concentration of Monoamines and Their Metabolites in the Discrete Brain Regions of Adolescent Mice Exposed to Social Defeat Stress and Subjected to Social Interaction Test 1 Day after the Last Social Defeat Stress Exposure Region Group 5-HT 5-HIAA Dopamine DOPAC HVA Noradorenaline MHPG Prefrontal Nontested cortex (PFC) Control 202.1 ± 7.2 208.6 ± 5.9 96.9 ± 27.9 87.4 ± 14.8 73.5 ± 6.6 246.6 ± 2.6 50.0 ± 1.6 Defeated 193.1 ± 19.1 229.8 ± 9.2 114.7 ± 27.1 76.4 ± 11.0 85.0 ± 6.8 275.6 ± 8.2* 53.5 ± 5.7 Tested Control 190.9 ± 11.2 305.6 ± 16.1** 122.0 ± 48.6 117.1 ± 25.7 113.1 ± 11.4 266.8 ± 7.1 65.8 ± 2.4 Defeated 256.9 ± 7.0## 207.1 ± 15.9## 153.9 ± 49.3 98.7 ± 35.9 106.4 ± 15.8 292.1 ± 8.2 72.0 ± 8.1 Nucleus Nontested accumbens Control 599.3 ± 51.4 348.2 ± 11.3 5839.0 ± 445.8 1279.5 ± 97.9 531.2 ± 40.8 174.6 ± 25.9 71.0 ± 2.4 (NAc) Defeated 549.7 ± 55.2 336.5 ± 18.4 6711.7 ± 664.9 905.4 ± 77.07 476.7 ± 62.2 245.2 ± 38.4 81.7 ± 6.2 Tested Control 794.2 ± 147.2 550.7 ± 70.0** 6845.1 ± 708.8 1456.0 ± 162.9 795.2 ± 91.6* 305.0 ± 54.2 108.1 ± 14.7* Defeated 846.9 ± 48.5 373.5 ± 21.2# 7368.4 ± 355.2 764.2 ± 54.2## 647.7 ± 28.8 342.5 ± 47.1 114.4 ± 8.5 Hippocampus Nontested (HIP) Control 286.4 ± 4.5 400.0 ± 12.2 11.2 ± 1.6 11.6 ± 0.8 30.1 ± 1.4 278.0 ± 6.5 69.1 ± 1.6 Defeated 305.7 ± 10.4 413.4 ± 20.0 15.5 ± 0.8 13.6 ± 1.6 28.3 ± 1.1 334.7 ± 6.4* 69.7 ± 6.3 Tested Control 271.9 ± 26.2 455.7 ± 36.0 14.5 ± 1.6 15.1 ± 2.6 37.4 ± 3.5 263.1 ± 17.0 73.0 ± 5.1 Defeated 303.4 ± 15.4 411.1 ± 19.4 21.3 ± 2.2# 14.6 ± 1.8 34.3 ± 1.5 328.8 ± 16.2## 80.8 ± 1.6 Amygdala Nontested (AMG) Control 426.9 ± 8.1 494.5 ± 16.4 265.6 ± 22.9 154.8 ± 17.9 82.4 ± 7.8 254.7 ± 4.4 72.3 ± 1.7 Defeated 423.2 ± 14.6 451.0 ± 20.8 311.8 ± 42.9 132.7 ± 16.5 78.1 ± 9.4 293.4 ± 8.2 76.6 ± 5.3 Tested Control 427.5 ± 12.7 636.7 ± 29.4** 279.1 ± 18.5 153.9 ± 12.3 96.9 ± 5.3 270.1 ± 6.4 88.5 ± 2.2 Defeated 447.4 ± 27.1 460.3 ± 31.4## 457.6 ± 76.8 155.3 ± 27.8 107.4 ± 14.4 306.4 ± 17.8 92.9 ± 7.6 Values are expressed as ng/g wet weight and are the means ± SEM (n = 8–9). The amounts of 5-HT, dopamine, noradrenaline, and their metabolites (5-HIAA, DOPAC, HVA, and MHPG) in the discrete brain regions were determined. Two-way ANOVA; 5-HT: F (3, 120) = 95.8, P < .01; F (3, 120) = 4.18, P < .01; F brain region group brain region × group (9, 120) = 2.63, P < .01, 5-HIAA: F (3, 120) = 77.0, P < .01; F (3, 120) = 22.8, P < .01; F (9, 120) = 2.09, P < .05, dopamine: F (3, 120) = 535.7, P < .01; brain region group brain region × group brain region F (3, 120) = 1.68, P = .18; F (9, 120) = 1.14, P = .34, DOPAC: F (3, 120) = 363.8, P < .01; F (3, 120) = 9.76, P < .01; F (9, 120) = 8.78, P < .01, HVA: group brain region × group brain region group brain region × group F (3, 120) = 312.4, P < .01; F (3, 120) = 7.70, P < .01; F (9, 120) = 4.53, P < .01, noradrenaline: F (3, 120) = 0.19, P = .90; F (3, 120) = 8.47, brain region group brain region × group brain region group * ** P < .01; F (9, 120) = 1.17, P = .32, MHPG: F (3, 120) = 21.0, P < .01; F (3, 120) = 13.6, P < .01; F (9, 120) = 1.21, P = .29. P < .05, P < .01 vs non- brain region × group brain region group brain region × group # ## tested control group,P < .05, P < .01 vs tested control group (Bonferroni’s test). Nontested, mice sacrificed without performing the social interaction test; tested, mice sacrificed immediately after social interaction test; control, mice exposed to an empty cage; defeated, mice exposed to an aggressive ICR mouse. decreased, respectively, in the tested defeated group compared Acute administration of desipramine, sertraline, and ari- with those in the tested control group. The NA concentration piprazole did not affect the decrease in time spent in the in the PFC or HIP and the MHPG concentration in the NAc were interaction zone in the second session to expose an unfamil- significantly increased in the nontested defeated and the tested iar ICR mouse when tested 1 day after the last stress exposure control groups, respectively, compared with those of the non- (Figure  3A1–3). When tested 15  days after the last stress expo- tested control group. Lastly, the NA concentration in the HIP was sure, their repeated administration also did not affect body significantly increased in the tested defeated group compared weight gain (data not shown) and the decrease in time spent in with that in the tested control group (Table 1). the interaction zone in the second session (Figure 3B1–3). In the first session of acute administration, there was no significant difference among the groups in the time spent in Effects of Antidepressants and Aripiprazole on the the interaction zone (data not shown), whereas the repeated Impairment of Social Behaviors in Mice Exposed to administration of 20 mg/kg desipramine and 0.003 and 0.01 mg/ Social Defeat Stress as Juveniles kg aripiprazole led to significantly increased time spent in the To investigate the role of monoaminergic neuronal systems in interaction zone in the first session compared with vehicle in the the impairment of social behaviors induced by social defeat defeated group [2-way ANOVA; desipramine: F (1, 70) = 3.62, defeat stress exposure as juveniles, desipramine (10 and 20  mg/kg P = .06; F (2, 70) = 1.11, P = .34; F (1, 70) = 8.53, P < .01, ser- drug defeat × drug i.p.), a NA reuptake inhibitor; sertraline (5 and 10 mg/kg i.p.), a traline: F (1, 60) = 2.00, P = .16; F (2, 60) = 0.28, P = .76; F defeat drug defeat × drug selective 5-HT reuptake inhibitor; and aripiprazole (0.003 and (1, 60) = 7.34, P < .01, aripiprazole: F (1, 96) = 0.66, P = .42; F (2, defeat drug 0.01  mg/kg i.p.), a DA receptor partial agonist, were adminis- 96) = 2.53, P = .09; F (1, 96) = 4.07, P < .05] (data not shown). defeat × drug tered once a day from 1  day after social defeat stress expo- sure for 15 days (Figure 3A). The doses used followed previous Additive Effect of Sertraline with Aripiprazole on the publications; desipramine at 20 mg/kg (p.o.) and sertraline at Impairment of Social Behaviors in Adolescent Mice 10 mg/kg (i.p.) attenuated depressive-like behaviors in a forced Exposed to Social Defeat Stress as Juveniles swim test (Noda et  al., 1997; Mouri et  al., 2012). Aripiprazole at 0.03  mg/kg (p.o.) attenuated phencyclidine-induced the Both clinical and preclinical studies have demonstrated adjunc- impairment of recognition memory (Nagai et  al., 2009); how- tive use of aripiprazole as an augmentation strategy when ever, it did not affect locomotor activity at 0.01  mg/kg (i.p.) combined with SSRIs (Kamei et  al., 2008; Bourin et  al., 2009). (Bourin et al., 2009). The present results shown in Figures 3A1–3 and 3B1–3 indicate Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 842 | International Journal of Neuropsychopharmacology, 2018 Figure  2. Changes in monoamine metabolisms in discrete brain regions of adolescent mice exposed to social defeat stress as juveniles. Changes in serotonin (A), dopamine (B), and noradrenaline (C) utilizations in brain regions of adolescent mice exposed to social defeat stress as juveniles. Data are expressed as a percentage of nontested control group (set at 100%). Each column represents the mean ± SEM (n = 8–9). Other details are shown in Table 1. Two-way ANOVA: (A) F (3, 120) = 2.21, brain region P = .09; F (3, 120) = 19.9, P < .01; F (9, 120) = 1.90, P = .60. (B) F (3, 120) = 1.02, P = .39; F (3, 120) = 7.00, P < .01; F (9, 120) = 0.28, P = .98. (C) group brain region × group brain region group brain region × group F (3, 120) = 6.06, P < .01; F (3, 120) = 2.94, P = .36; F (9, 120) = 1.20 P = .30. *P < .05, **P < .01 vs nontested control group, #P < .05, ##P < .01 vs tested control brain region group brain region × group group (Bonferroni’s test). Nontested: mice sacrificed without the social interaction test, tested: mice sacrificed immediately after social interaction test, control: mice exposed to an empty cage, defeated: mice exposed to an aggressive ICR mouse. exposure to social defeat stress as juveniles leads to the treat- Discussion ment-resistant impairment of social behaviors in adolescents, Adult rodents exposed to social defeat stress repeatedly dis- which is potentially caused by dysfunction of serotonergic and play anxiety- and depressive-like behaviors (Kudryavtseva et al., dopaminergic neuronal systems (Table  1; Figure  2). To investi- 1991; Avgustinovich et al., 2005) such as the impairment of social gate the effect of combined administration of sertraline and ari- behaviors (Berton et al., 2006Tsanko ; va et al., 2006), resembling piprazole on the impairment of social behaviors, we used their the clinical symptoms of stress-related psychiatric disorders. ineffective doses, which were 10 mg/kg and 0.01 mg/kg, respec- In the present study, mice exposed to social defeat stress as tively ( Figure 3A4 and B4). juveniles showed the persistent impairment of social behav- In the second session, acute combined administration of iors in adolescents, which is consistent with our previous find- sertraline with aripiprazole did not affect the impairment of ing (Mouri et al., 2018). The impairment of social behaviors was social behaviors when tested 1 day after the last stress expo- not due to motor dysfunction, since the mice showed no differ - sure, whereas repeated combined administration significantly ence in locomotor activity in the first session of social interac- attenuated it when tested 15 days after that (Figures 3A4 and tion test regardless of their exposure to social defeat stress. The B4). In the first session, however, there was no significant impairment of social behaviors was also replicated even when difference between groups in the time spent in the interac- the C57BL/6J (same strain) mouse was present 1  day after last tion zone when tested at 1 and 15  days after the last stress stress exposure (Mouri et al., 2018). Thus, it is unlikely that the exposure, except for repeated combined administration in the defeated mice did not approach the unfamiliar target ICR mouse defeated group at 15 days [2-way ANOVA; when tested 15 days: only because of the social fear response to the aggressor. On the F (1, 69) = 0.27, P = .60; F (1, 69) = 2.34, P = .13; F (1, Defeat Drug Defeat × Drug other hand, social defeat stress exposure as juveniles did not 69) = 0.16, P = .68, when tested 15 day: F (1, 69) = 1.05, P = .31; Defeat induce pronounced anxiety-like behaviors (Mouri et  al., 2018). F (1, 69) = 2.88, P = .09; F (1, 69) = 3.86, P = .05] (data not Drug Defeat × Drug The immobility in the forced swimming test was enhanced shown). between 1 day and 4 weeks after the last stress, suggesting that Combined administration of sertraline and aripiprazole did vulnerability against intense stress was generated by repeated not affect body weight gain (data not shown) and the explora- exposure to juvenile stress (Mouri et  al., 2018). Therefore, tory activity (supplemental Figure S2). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 843 Figure  3. Effects of antidepressants and aripiprazole on the impairment of social behaviors in adolescent mice exposed to social defeat stress as juveniles. From 1 day after the last stress exposure, the i.p. administration of vehicle (veh), desipramine 10 or 20 mg/kg (A1 and B1), sertraline 5 or 10 mg/kg (A2 and B2), aripiprazole 0.003 or 0.01 mg/kg (A3 and B3) or combined administration of sertraline 10 mg/kg with aripiprazole 0.01 mg/kg (A4 and B4) was started and continued once a day for 15 days. The social interaction test was performed 1 day and 15 days after the last stress exposure. Each column represents the mean ± SEM (n = 8–24). Two-way ANOVA. (A1) F (1, 70) = 94.7, P < .01; F (2, 70) = 1.23, P = .30; F (1, 70) = 0.51, P = .82. (A2) F (1, 60) = 5.28, P < .05; F (2, 60) = 3.30, P < .05; F (1, 60) = 3.77, P = .57. defeat drug defeat × drug defeat drug defeat × drug (A3) F (1, 96) = 33.3, P < .01; F (2, 96) = 3.10, P < .05; F (1, 96) = 0.17, P = .68. (A4) F (1, 69) = 9.83, P < .01; F (1, 69) = 0.95, P = .33; F (1, 69) = 0.57, P = .45. defeat drug defeat × drug defeat drug defeat × drug (B1) F (1, 70) = 13.1, P < .01; F (2, 70) = 1.84, P = .17; F (1, 70) = 0.17, P = .68. (B2) F (1, 60) =4.58, P < .05; F (2, 60) = 1.87, P = .16; F (1, 60) = 1.48, P = .23. (B3) defeat drug defeat × drug defeat drug defeat × drug F (1, 96) = 18.6, P < .01; F (2, 96) = 0.73, P = .49; F (1, 96) = 1.34, P = .25. (B4) F (1, 69) = 6.80, P < .05; F (1, 69) = 0.14, P = .71; F (1, 69) = 10.1, P < .01. ##P < .01 defeat drug defeat × drug defeat drug defeat × drug vs vehicle-administrated control group, †P < .05 vs vehicle-administrated defeated group (Bonferroni’s test). control: mice exposed to an empty cage, defeated: mice exposed to an aggressive ICR mouse. juvenile rodents exposed to social defeat stress repeatedly NAc, HIP, and AMG was decreased in adolescent mice exposed to display depressive-like but not anxiety-like behaviors, and the social defeat stress as juveniles following the social interaction impairment of social behaviors by social defeat stress might be test. Namely, no change in DA metabolism of the tested con- caused by decrease of sociality rather than anxiety to the -tar trol group was observed, while the metabolism was significantly get mouse. In addition, the present stressed mouse model may decreased on social defeat stress exposure in the tested mice be useful as a juvenile stress-based experimental model for the (the tested defeated group) compared with that in the tested study of psychiatric disorders in adolescents. control group. Stress-induced inhibition of DA release in the The detailed mechanisms of social behavioral changes in NAc can explain the impaired defensive reactions under aver - this model have not been elucidated yet. However, it has been sive conditions observed following stressful experiences (Cabib suggested that monoaminergic neuronal systems are impor - and Puglisi-Allegra, 1996). Taken together with these reports tant modulators of the responses to stress (Torres et al., 2002). (Cabib and Puglisi-Allegra, 1996; Firk and Markus, 2007), our Continued or chronic stress exposure is found to have a nega- findings suggest that the not only serotonergic, but also dopa- tive influence on the serotonergic neuronal system and may minergic neuronal systems in adolescent mice are impaired by increase the 5-HT sensitivity or vulnerability as a compensatory social defeat stress exposure as juveniles. There are functional response (Firk and Markus, 2007). In this model, the 5-HT metab- changes associated with the decreased the utilization of 5-HT olism in the PFC and AMG of the nontested control group were and DA, which might be involved in the impairment of social increased following the social interaction test, whereas there behaviors. This could be a model of decreased interest as the were no changes in NA and DA metabolisms. Interestingly, an symptom of depression. increase in the utilization of 5-HT was not observed following The utilization of DA was increased in the PFC and NAc of the social interaction test in mice exposed to the stress. Thus, adolescent mice exposed to social defeat stress (Tanaka et  al., these findings suggest that the serotonergic neuronal dysfunc- 2012). The reason for this discrepancy is unknown but may be tion is involved in the expression of impaired social behaviors. because of difference in aging between samples exposed to social Meanwhile, the utilization of not only 5-HT but also DA in the defeat stress at 3 weeks (juvenile) and 6 weeks (adolescent). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 844 | International Journal of Neuropsychopharmacology, 2018 Prominent developmental transformations are seen in the PFC changes in the utilizations of the 5-HT (P < .05), and DA (P = .08), and limbic regions of the brain of adolescents across a variety NA (P = .06) in the AMG (supplemental Figure S1) but not in other of species; alterations include an apparent shift in the balance brain regions (PFC, NAs, and HIP: data not shown) 15 days after between the mesocortical and mesolimbic dopaminergic neu- the last social defeat stress exposure, indicating monoaminergic ronal system (Spear, 2000). Different development transforma- neuronal dysfunction in the AMG. Multiple functional changes tions in mesocortical and mesolimbic dopaminergic neuronal in the monoaminergic neuronal systems of the AMG occurred systems between juvenile and adolescent mice exposed to over the 15 days and led to persistent impairment of the social social defeat stress may be involved. behaviors in the adolescent mice. Repeated administration Acute or repeated administration of traditional antidepres- of a combination of sertraline and aripiprazole prevented the sants have been shown to be effective in many animal models of development of multiple functional changes in monoaminer- MDD (Caldarone et al., 2015). Repeated administration of parox- gic neuronal systems, leading to reversal of social impairment. etine, which is used widely in humans, attenuated impairment Emotionally related learning, including stress exposure events, of social interaction in adult, defeated mice (Xu et  al., 2018). In is mediated through the interactions of the basolateral HIP and the present study, acute and repeated administration of desipra- AMG formation (Benes, 2010). We reported that the stress expo- mine and sertraline did not attenuate the persistent impairment sure induced the persistent impairment of social behaviors of social behaviors in adolescent mice exposed to social defeat associated with suppression of the hippocampal neurogenesis stress as juveniles. Our findings suggest that exposure to social (Mouri et al., 2018). In the present study, we found the changes defeat stress as juveniles induces an antidepressant-resistant in the utilizations of the 5-HT and DA in the AMG 15 days after impairment of social behaviors in adolescents. Antidepressants the last social defeat stress exposure (supplemental Figure S1). are widely used in the treatment of depression in adolescents, Thus, repeated administration of a combination of sertraline although there are antidepressant-resistant in adolescents and aripiprazole may improve monoaminergic neuronal dys- (Cipriani et  al., 2016). Augmentation pharmacotherapy refers to functions in the HIP and/or AMG 1 and/or 15 days after the stress the addition of drugs that are not standard antidepressants to exposure. Further studies are needed to investigate the effect enhance the effect of a classical antidepressant drug (Carvalho of social defeat stress exposure in monoaminergic neuronal et  al., 2007). Clinically, antidepressant activity of antipsychotics systems of the HIP-AMG pathways and morphological changes, has been observed when administered either alone or in com- such as spine densities and dendritic lengths, during develop- bination with an antidepressant (Kamei et  al., 2008). DA-D and ment of monoaminergic neuronal systems (Lyttle et  al., 2015; D receptor agonists have been tested as augmenting agents in Suri et al., 2015). antidepressant-resistant forms of MDD (Carvalho et  al., 2007). In the present study, there were no significant changes in Aripiprazole is an atypical antipsychotic with a novel pharma- NA metabolism in the all brain regions of the mice exposed to cological profile, acting as a partial DA-D and D receptor ago- social defeat stress when the all groups were compared. Thus, 2 3 nist (Bourin et al., 2009). In the present study, however, acute and it is unlikely that the impairment of social behaviors is due to repeated administration of aripiprazole itself did not attenuate changes in the noradrenergic neuronal system relative to that the persistent impairment of social behaviors in adolescent mice of the controls, although the noradrenergic neuronal system exposed to social defeat stress as juveniles despite the DA hypo- has been explicitly implicated in pathophysiological conditions function observed in the defeated mice. The functional changes induced by the stress exposure (Glavin, 1985). Further, previ- in the utilization of 5-HT and DA were observed in adolescent ous studies have shown that NA transporter-knockout mice mice exposed to social defeat stress as juveniles. These results are resistant to the impairment of social behaviors induced by indicate that multiple functional changes in monoaminergic social defeat stress exposure (Haenisch et al., 2009). It remains neuronal systems are involved in the treatment-resistant impair - unclear whether noradrenergic neuronal systems are involved ment of social behaviors in adolescent mice exposed to social in the treatment-resistant impairment of social behaviors in defeat stress as juveniles. Treatment with a combination of atypi- adolescent mice exposed to social defeat stress as juveniles. The cal antipsychotic drugs and SSRIs had antidepressant effects in mechanisms of additive effect also remain unclear and might patients who did not respond to SSRI monotherapy (Kamei et al., be mediated by multiple receptor properties and other neuronal 2008). Previous studies have indicated that aripiprazole combined systems including the glutamatergic and cholinergic neuronal with inactive doses of antidepressants attenuated depressive-like systems. Aripiprazole acts as not only a partial agonist at the behaviors in a forced swim test (Bourin et al., 2009). At noneffec- DA-D and D receptors but also as a partial agonist at the sero- 2 3 tive doses individually, repeated administration of a combination tonin 5-HT receptors and an antagonist at the serotonin recep- 1A of sertraline and aripiprazole showed additive effects without tors (Bourin et al., 2009). Both monoaminergic and glutamatergic affecting body weight gain and the exploratory activity on the (Sanacora et al., 2012) as well as cholinergic (Mineur et al., 2013) impairment of social behaviors in adolescent mice exposed to neuronal systems have driven the research on the impairment social defeat stress as juveniles in the present study. Thus, the of social behaviors induced by social defeat stress exposure. The combined administration of sertraline with aripiprazole may be additive effect may be mediated, at least partly, by the activation useful as a new treatment strategy for treatment-resistant of of the serotonergic and dopaminergic neuronal systems. Further stress stress-related psychiatric disorders. studies are needed to investigate the complex mechanisms It is unclear why repeated but not acute administration of behind the functional changes in both the noradrenergic and a combination of sertraline and aripiprazole attenuates the serotonergic/dopaminergic neuronal systems, including recep- impairment of social behaviors induced by social defeat stress tor functions and other neuronal systems, leading to the devel- exposure as juveniles, whereas the serotonergic and dopa- opment of treatment-resistant impairment of social behaviors. minergic neuronal systems were impaired 1  day after the last Aripiprazole is a dopaminergic neuronal system stabilizer; exposure to social defeat stress. There are only a few clinical namely, a drug that can enhance dopaminergic neuronal activity or preclinical studies that have assessed the effects of chronic when it is diminished or suppress it when it is increased (Stahl, administration of aripiprazole in combination with antidepres- 2001a, 2001b). Bourin et  al. (2009) referred that the combina- sants in adolescent depressed patients or in mice. We found tion of aripiprazole and selective serotonin reuptake inhibitors Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 845 (SSRIs) in outpatients with depression who did not experience Avgustinovich DF, Kovalenko IL, Kudryavtseva NN (2005) A model significant clinical improvement after taking antidepressants of anxious depression: persistence of behavioral pathology. alone was performed in clinical trials (Papakostas et  al., 2004; Neurosci Behav Physiol 35:917–924. Simon and Nemeroff, 2005; Marcus et al., 2008). These findings Benes FM (2010) Amygdalocortical circuitry in schizophre- suggest that aripiprazole adjunction could be used as an aug- nia: from circuits to molecules. Neuropsychopharmacology mentation strategy when combined with SSRIs (Bourin et  al., 35:239–257. 2009). Bourin et  al (2009) demonstrated that combined admin- Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo istration of subactive doses of antidepressants (which activate SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia the serotonergic system) with aripiprazole (which activates the LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the dopaminergic system) induced an antidepressive-like effect in a mesolimbic dopamine pathway in social defeat stress. mouse model of depression. Thus, we speculated that aripipra- Science 311:864–868. zole may work as an agonistic rather than antagonistic for dopa- Bourin M, Chenu F, Prica C, Hascoët M (2009) Augmentation mine-D receptor in the present experiment. effect of combination therapy of aripiprazole and antidepres- In conclusion, exposure to social defeat stress as juveniles sants on forced swimming test in mice. Psychopharmacology induces the treatment-resistant impairment of social behaviors (Berl) 206:97–107. in adolescents through the functional changes in the seroton- Boyarskikh UA, Bondar NP, Filipenko ML, Kudryavtseva NN (2013) ergic and dopaminergic neuronal systems. Administration of a Downregulation of serotonergic gene expression in the Raphe combination of sertraline and aripiprazole may be useful as a nuclei of the midbrain under chronic social defeat stress in new treatment strategy in adolescents, who had been exposed male mice. 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J Neurosci (MEXT) of Japan, Grant-in-Aid for the Strategic Research Program 30:16453–16458. for Brain Sciences from Japan Agency for Medical Research and Carvalho AF, Cavalcante JL, Castelo MS, Lima MC (2007) development, AMED, The Adaptable and Seamless Technology Augmentation strategies for treatment-resistant depression: Transfer Program Through Target-driven R&D, Japan Science and a literature review. J Clin Pharm Ther 32:415–428. Technology Agency (grant no. AS251Z03018), Meijo University Chen P, Fan Y, Li Y, Sun Z, Bissette G, Zhu MY (2012) Chronic Research Institute grant, and Smoking Research Foundation social defeat up-regulates expression of norepinephrine Grant for Biomedical Research. transporter in rat brains. Neurochem Int 60:9–20. 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Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant Impairment of Social Behaviors Induced by Social Defeat Stress Exposure as Juveniles

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Abstract

Background: Extensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles. Methods: Juvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1  day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15  days. Social behaviors were assessed at 1 and 15  days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress. Results: Stress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects. Conclusions: These findings suggest that social defeat stress exposure as juveniles induces the treatment-resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress- related psychiatric disorders in adolescents with adverse juvenile experiences. Keywords: social defeat stress, juvenile, adolescent, social behaviors, monoaminergic neuronal system Received: January 5, 2018; Revised: March 20, 2018; Accepted: March 28, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 837 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 838 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Monoaminergic neuronal systems have attracted the attention of researchers with regard to the impairment of social behaviors induced by social defeat stress exposure as adults. However, the importance of monoaminergic neuronal systems in the impair - ment of social behaviors induced by exposure to social defeat stress as juveniles remains poorly understood; thus, in the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles. Exposure to social defeat stress as juveniles leads to the treatment-resistant impairment of social behaviors in adolescents, because of dysfunction of the serotonergic and dopaminergic neuronal systems. Repeated administration of a combination of sertraline and aripiprazole showed additive effects in attenuating this impairment of social behaviors. This may be useful as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adoles- cents with adverse juvenile experiences. Introduction Adverse juvenile experiences, including physical or sexual the role of monoaminergic neuronal systems in the impairment violence and neglect, often induce adverse mental health out- of social behaviors induced by social defeat stress exposure as comes later in life (Afifi, 2011; Annerback et al., 2012; McKenzie juveniles remains unclear. and Scott, 2012). Epidemiological studies have demonstrated The present study was designed to investigate the role of that adverse juvenile experiences increase the risk for stress- monoaminergic neuronal systems in the impairment of social related psychiatric disorders, particularly major depressive dis- behaviors induced by social defeat stress exposure as juveniles. order (MDD), anxiety disorder, and posttraumatic stress disorder We determined the functional and neurochemical changes in (Weber et  al., 2008; Weich et  al., 2009; McLaughlin et  al., 2010). the monoaminergic neuronal systems of mice exposed to social These psychiatric disorders induced by adverse juvenile experi- defeat stress as juveniles using biochemical techniques. We also ences frequently involve marked dysfunction in social activity investigated the effect of antidepressants and aripiprazole on during adolescence and adulthood (Sandi and Haller, 2015). the impairment of social behaviors in adolescent mice exposed The monoaminergic neuronal system has attracted increas- to social defeat stress as juveniles. ing attention of researchers in the field of stress-related psychi- atric disorders (Flugge, 2000 Pitteng ; er and Duman, 2008; Krystal Materials and Methods and Neumeister, 2009). Polymorphism of the serotonin (5-HT) transporter (5-HTTLPR genotype) has been reported to be a sus- Animals ceptibility factor for posttraumatic stress disorder in the inter - action between adult traumatic events and childhood adversity Male C57BL/6J and ICR mice were obtained from Japan SLC, Inc. (Steckler and Risbrough, 2012). Further, monoaminergic neu- Juvenile, male C57BL/6J mice (3 weeks old) were used to expo- ronal dysregulation may contribute vulnerability to stress as a sure to social defeat stress. Aggressive, male ICR mice (over 7 factor in the development of anxiety disorders, because 5-HT weeks old) for social defeat stress were screened based on the reuptake inhibitors and dual 5-HT/noradrenaline (NA) reuptake duration of attacks on C57BL/6J mice, with more than 1/10 min- inhibitors are effective in treating anxiety disorders (Morilak utes as the inclusion criterion. Unfamiliar target male ICR mice and Frazer, 2004). Low CSF levels of 5-hydroxyindoleacetic acid (over 4–6 weeks old) were used for the social interaction test. (5-HIAA), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), They were housed in plastic cages in a regulated environment and homovanilic acid (HVA) have been hypothesized to be (23°C ± 1°C, 50 ± 5% humidity), with a 12-hour-light/-dark cycle involved in MDD, although the published literature is contra- (lights on at 9:00 am). Food (CE2; Clea Japan Inc.) and tap water dictory (Placidi et al., 2001). Extensive investigation on the role were available ad libitum. All experiments were conducted in of monoaminergic neuronal systems has also been performed accordance with the Guidelines for Animal Experiments of the in rodents exposed to social defeat stress as adults (Krishnan Nagoya University Graduate School of Medicine. Procedures et al., 2007; Cao et al., 2010; Chen et al., 2012; Boyarskikh et al., involving animals and their care were conformed to the 2013). international guidelines set out in the National Institutes of Mice exposed to social defeat stress as adults display the Health’s Guide for the Care and Use of Laboratory Animals (NIH impairment of social behaviors (Berton et  al., 2006; Tsankova Publications No. 8023, revised 1978). et  al., 2006). Previous studies have shown that tryptophan hydroxylase 2 knockin mice, which show 60% to 80% reduc- Drug Administration tion in brain 5-HT, have increased susceptibility to social defeat Desipramine hydrochloride, sertraline hydrochloride, and ari- stress (Nakayama et al., 2003). The impairment of social behav- iors induced by social defeat stress exposure is dependent on piprazole were purchased from Sigma-Aldrich, Tokyo Chemical Industry Co, Ltd, and Wako Pure Chemical Industries, Ltd, the mesolimbic dopamine (DA) circuit (Tanaka et  al., 2012). In addition, NA transporter-knockout mice resist the impairment respectively. Desipramine and sertraline were dissolved in dis- tilled water. Aripiprazole was dissolved in 100% acetic acid and of social behaviors induced by social defeat stress exposure (Haenisch et  al., 2009). These findings suggest that brain mon- diluted with distilled water. From 1  day after the last social defeat stress exposure, i.p. oaminergic neuronal systems are involved in the impairment of social behaviors induced by social defeat stress exposure. administration of 10 and 20  mg/kg desipramine, 5 and 10  mg/ kg sertraline, or 0.003 and 0.01  mg/kg aripiprazole was com- We previously found that juvenile mice were more vulnerable to the impairment of social behaviors induced by social defeat menced; this treatment was performed once a day for 15 days. The administration volume was 10 mL/kg per mouse. stress exposure than adult mice (Mouri et  al., 2018). However, Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 839 ice-cold plate according to the atlas (Paxinos and Franklin, 2004). Social Defeat Stress Each tissue sample was quickly frozen on dry ice, weighed, and Social defeat stress exposure was carried out according to stored in a deep freezer at -80°C until assay. the method outlined in previous reports (Berton et  al., 2006; Krishnan et  al., 2007) with minor modifications. Prior to social Determination of Monoamines and Their defeat stress, an aggressive ICR mouse was habituated to social Metabolites defeat stress cages for 10 minutes. C57BL/6J mice (3 weeks old) were exposed to a different aggressive ICR mouse for 10 minutes The concentrations of monoamines and their metabolites were each day for 10 consecutive days. The pairing of defeated and determined using a high-performance liquid chromatography aggressive mice was randomized daily to minimize the effects system with an electrochemical detector (Eicom) as described in of variability in aggression that the mice were exposed to. previous reports (Noda et al., 1997, 1998). Briefly, each frozen tis- Defeat was defined as the display of defensive behaviors by sue sample was homogenized with an ultrasonic processor (475 C57BL/6J mice, such as escape and submissive postures during W, Model XL2020, Heat Systems Inc.) in 350 μL of 0.2 M perchloric physical attacks by an aggressive mouse. Submissive posture acid containing isoproterenol (internal standard). The homoge- was defined as standing upright with the belly exposed to the nate was placed in ice for 30 minutes and then centrifuged at aggressor. The duration of defensive behaviors was recorded 20 000 × g for 15 minutes at 0°C. The supernatant was mixed with according to our previous report (Mouri et  al., 2018). After 10 1 M sodium acetate to adjust the pH to 3.0 and then injected minutes, an aggressive mouse was separated from the defeated into a liquid chromatography system equipped with a reversed- mouse to avoid habituation to the defeated mouse and placed in phase ODS-column (3 × 150  mm, diameter of stationary phase its group-housed home cage for the next 24 hours. grains 5 μm: Eicompak SC-5ODS, Eicom) and an electrochemi- We previously found that mice exposed to a nonaggressive cal detector (model ECD-700, Eicom). The column temperature ICR mouse (undefeated mice) as well as an empty cage (control was maintained at 25°C, and the detector potential was set at mice) for 10 consecutive days showed significantly increased +750 mV. The mobile phase consists of 0.1 M citric acid and 0.1 duration at the interaction zone in the second session com- M sodium acetate, pH 3.5, containing 15% methanol, 220  mg/L pared with that in the first session (Mouri et al., 2018). Thus, it sodium-l-octanesulfonate, and 5  mg/L ethylenediaminetet- is unlikely that defeated mice were habituated to expose ICR raacetic acid; the flow rate was 0.5 mL/min. Data were collected mouse during social defeat stress and did not approach familiar and analyzed with the PowerChrom v2.6.4 software (eDAQ). target ICR mouse. Control mice were exposed to an empty cage as described in Statistical Analysis our previous report (Mouri et al., 2018). All results are expressed as the mean± SEM for each group. Statistical significance was determined using 1-way or 2-way Social Interaction Test ANOVA followed by Bonferroni’s test. The Student’s t test was used to compare 2 sets of data. P <.05 w as taken to indicate sig- The adolescent mice (4 or 6 weeks old) were subjected to the nificance. Data were analyzed with SPSS 24 software (IBM). social interaction test at 1 and 15 days after the last stress expo- sure. The social interaction test was performed from 10:00 am to 5:00 pm in a sound-attenuated room, as described in our pre- Results vious report (Mouri et al., 2018). The apparatus consisted of an open gray nonreflecting acrylic box (W42 × D42 × H30 cm) and the The Impairment of Social Behaviors in Adolescent transparent Plexiglas enclosure (W10 × D6.5 × H30  cm) with 30 Mice Exposed to Social Defeat Stress as Juveniles holes (10 mm in diameter). A lightbulb (54 W), not directly seen by the mouse, was attached to the upper part of the apparatus Adolescent, male C57BL/6J mice were exposed to social defeat and provided constant illumination of approximately 20 lux. stress as juveniles for 10 consecutive days. When juvenile The social interaction test consisted of 2 sessions: in the first mice body weight was measured immediately after the stress session, the mouse was allowed to freely explore and habitu- exposure of 10 consecutive days, the stress exposure did not ate to the test environment for 30 minutes in the absence of affect body weight gain (data not shown), in consistent with an unfamiliar target ICR mouse, in consistent with a previous a previous report (Mouri et  al., 2018). One day after the last report (Mouri et  al., 2018). This was done to reduce the time stress exposure, mice were subjected to the social interac- spent in the interaction zone by exploring the apparatus itself tion test. In the first session without an unfamiliar ICR mouse, during the second session. The second session commenced 1 there was no significant difference between groups in the minute after the first session, and the mouse was returned to time spent in the interaction zone and engaging in explora- the apparatus for 5 minutes in the presence of an unfamiliar tory activity within the apparatus (Figure  1A). In the second target ICR mouse. During the test, the time spent in the interac- session, control mice approached the unfamiliar target ICR tion zone (6 cm width) was recorded for the last 5 minutes of the mouse and showed significantly increased time spent in the first (target absent) and for the 5 minutes of the second (target interaction zone than in the first session (Figure 1A). However, present) sessions, using a video-tracking system (EthoVision XT; in the second session, the mice exposed to the stress as juve- Noldus Information Technology). niles for 10 consecutive days spent significantly less time in the interaction zone than the control group, although there were no difference in exploratory activity between control and Preparation of Brain Samples defeated groups (Figure 1A). When tested 15  days after the last stress exposure, mice Each mouse was killed immediately before or soon after the social interaction test. Their brains were rapidly removed and exposed to the stress as juveniles still spent less time in the interaction zone in the second session, although there was no the prefrontal cortex (PFC), nucleus accumbens (NAc), hip- pocampus (HIP), and amygdala (AMG) were dissected out on an difference in exploratory activity between control and defeated Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 840 | International Journal of Neuropsychopharmacology, 2018 groups (Figure  1B). There was also no significant difference group (Figure  2A). In the PFC, NAc, and AMG, there was a sig- between groups in the time spent in the interaction zone and nificant decrease in the 5-HIAA/5-HT ratio in the tested defeated engaging in exploratory activity within the apparatus in the group compared with that in tested control group (Figure  2A). first session (Figure 1B). These results indicate that social defeat There were no significant changes in the 5-HIAA/5-HT ratio in stress exposure as juveniles induces the persistent impairment the HIP when all groups were compared (Figure 2A). No changes of social behaviors in adolescents. in the (DOPAC + HVA)/DA ratio (DA metabolism) were observed in the tested control group (Figure 2B), whereas the ratio in the NAc, HIP, and AMG was significantly decreased in the both non- Changes in Monoamine Metabolisms in Brain tested and tested defeated groups compared with that in the cor - Regions of Adolescent Mice Exposed to Social Defeat responding control groups, respectively (Figure  2B). There were Stress as Juveniles no significant changes in the MHPG/NA ratio (NA metabolism) in To examine the influence of social defeat stress exposure as the all brain regions when all groups were compared (Figure 2C). juveniles on monoaminergic neuronal systems, we measured Significant changes in the concentrations of monoamines the concentrations of monoamines and their metabolites in the and their metabolites were observed as follows:  the 5-HIAA PFC, NAc, HIP, and AMG immediately before (nontested group) or concentration in the PFC, NAc, and AMG was significantly after (tested group) the social interaction test (Tabl ). The e 1 ratios increased in the tested control group compared with that in the of 5-HIAA/5-HT, [3, 4-dihydroxyphenyl acetic acid (DOPAC) + nontested control group. The increase in 5-HIAA concentration HVA]/DA, and MHPG/NA, which are used as indices of the 5-HT, in the PFC, NAc, and AMG was significantly decreased in the DA, and NA turnover rates, were calculated in the PFC, NAc, HIP, tested defeated group compared with the tested control group. and AMG of the nontested and tested groups (Figure 2). The 5-HT concentration in the PFC was significantly increased A significant increase in the 5-HIAA/5-HT ratio (5-HT metab- in the tested defeated group compared with that in the tested olism) was observed in the PFC and AMG of the tested con- control group. The HVA concentration in the NAc was signifi- trol group compared with that of the nontested control group cantly increased in the tested control group compared with (Figure  2A). Such significant increase in the 5-HIAA/5-HT ratio that in the nontested control group. The DA and DOPAC con- was not observed in the PFC and AMG of the tested defeated centrations in the HIP and NAc were significantly increased and Figure 1. The impairment of social behaviors in adolescent mice exposed to social defeat stress as juveniles. (A) Duration at interaction zone (left) and exploratory activity (right) 1 day after the last stress exposure. (B) Duration at interaction zone (left) and exploratory activity (right) 15 days after the last stress exposure. Each col- umn represents the mean ± SEM (n = 12–15). Two-way ANOVA: duration at interaction zone: (A) F (1, 25) = 2.10, P = .16; F (1, 25) = 1.08, P = .31; F (1, 25) = 13.7, defeat session defeat × session P < .01. (B) F (1, 25) = 7.16, P = .13; F (1, 25) = 0.57, P = .46; F (1, 25) = 22.3, P < .01. **P < .01 vs corresponding control in the first session (Student’s t test). ##P < .01 defeat session defeat × session vs control group (Student’s t test). Control: mice exposed to an empty cage, defeated: mice exposed to an aggressive ICR mouse. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 841 Table 1. Changes in Concentration of Monoamines and Their Metabolites in the Discrete Brain Regions of Adolescent Mice Exposed to Social Defeat Stress and Subjected to Social Interaction Test 1 Day after the Last Social Defeat Stress Exposure Region Group 5-HT 5-HIAA Dopamine DOPAC HVA Noradorenaline MHPG Prefrontal Nontested cortex (PFC) Control 202.1 ± 7.2 208.6 ± 5.9 96.9 ± 27.9 87.4 ± 14.8 73.5 ± 6.6 246.6 ± 2.6 50.0 ± 1.6 Defeated 193.1 ± 19.1 229.8 ± 9.2 114.7 ± 27.1 76.4 ± 11.0 85.0 ± 6.8 275.6 ± 8.2* 53.5 ± 5.7 Tested Control 190.9 ± 11.2 305.6 ± 16.1** 122.0 ± 48.6 117.1 ± 25.7 113.1 ± 11.4 266.8 ± 7.1 65.8 ± 2.4 Defeated 256.9 ± 7.0## 207.1 ± 15.9## 153.9 ± 49.3 98.7 ± 35.9 106.4 ± 15.8 292.1 ± 8.2 72.0 ± 8.1 Nucleus Nontested accumbens Control 599.3 ± 51.4 348.2 ± 11.3 5839.0 ± 445.8 1279.5 ± 97.9 531.2 ± 40.8 174.6 ± 25.9 71.0 ± 2.4 (NAc) Defeated 549.7 ± 55.2 336.5 ± 18.4 6711.7 ± 664.9 905.4 ± 77.07 476.7 ± 62.2 245.2 ± 38.4 81.7 ± 6.2 Tested Control 794.2 ± 147.2 550.7 ± 70.0** 6845.1 ± 708.8 1456.0 ± 162.9 795.2 ± 91.6* 305.0 ± 54.2 108.1 ± 14.7* Defeated 846.9 ± 48.5 373.5 ± 21.2# 7368.4 ± 355.2 764.2 ± 54.2## 647.7 ± 28.8 342.5 ± 47.1 114.4 ± 8.5 Hippocampus Nontested (HIP) Control 286.4 ± 4.5 400.0 ± 12.2 11.2 ± 1.6 11.6 ± 0.8 30.1 ± 1.4 278.0 ± 6.5 69.1 ± 1.6 Defeated 305.7 ± 10.4 413.4 ± 20.0 15.5 ± 0.8 13.6 ± 1.6 28.3 ± 1.1 334.7 ± 6.4* 69.7 ± 6.3 Tested Control 271.9 ± 26.2 455.7 ± 36.0 14.5 ± 1.6 15.1 ± 2.6 37.4 ± 3.5 263.1 ± 17.0 73.0 ± 5.1 Defeated 303.4 ± 15.4 411.1 ± 19.4 21.3 ± 2.2# 14.6 ± 1.8 34.3 ± 1.5 328.8 ± 16.2## 80.8 ± 1.6 Amygdala Nontested (AMG) Control 426.9 ± 8.1 494.5 ± 16.4 265.6 ± 22.9 154.8 ± 17.9 82.4 ± 7.8 254.7 ± 4.4 72.3 ± 1.7 Defeated 423.2 ± 14.6 451.0 ± 20.8 311.8 ± 42.9 132.7 ± 16.5 78.1 ± 9.4 293.4 ± 8.2 76.6 ± 5.3 Tested Control 427.5 ± 12.7 636.7 ± 29.4** 279.1 ± 18.5 153.9 ± 12.3 96.9 ± 5.3 270.1 ± 6.4 88.5 ± 2.2 Defeated 447.4 ± 27.1 460.3 ± 31.4## 457.6 ± 76.8 155.3 ± 27.8 107.4 ± 14.4 306.4 ± 17.8 92.9 ± 7.6 Values are expressed as ng/g wet weight and are the means ± SEM (n = 8–9). The amounts of 5-HT, dopamine, noradrenaline, and their metabolites (5-HIAA, DOPAC, HVA, and MHPG) in the discrete brain regions were determined. Two-way ANOVA; 5-HT: F (3, 120) = 95.8, P < .01; F (3, 120) = 4.18, P < .01; F brain region group brain region × group (9, 120) = 2.63, P < .01, 5-HIAA: F (3, 120) = 77.0, P < .01; F (3, 120) = 22.8, P < .01; F (9, 120) = 2.09, P < .05, dopamine: F (3, 120) = 535.7, P < .01; brain region group brain region × group brain region F (3, 120) = 1.68, P = .18; F (9, 120) = 1.14, P = .34, DOPAC: F (3, 120) = 363.8, P < .01; F (3, 120) = 9.76, P < .01; F (9, 120) = 8.78, P < .01, HVA: group brain region × group brain region group brain region × group F (3, 120) = 312.4, P < .01; F (3, 120) = 7.70, P < .01; F (9, 120) = 4.53, P < .01, noradrenaline: F (3, 120) = 0.19, P = .90; F (3, 120) = 8.47, brain region group brain region × group brain region group * ** P < .01; F (9, 120) = 1.17, P = .32, MHPG: F (3, 120) = 21.0, P < .01; F (3, 120) = 13.6, P < .01; F (9, 120) = 1.21, P = .29. P < .05, P < .01 vs non- brain region × group brain region group brain region × group # ## tested control group,P < .05, P < .01 vs tested control group (Bonferroni’s test). Nontested, mice sacrificed without performing the social interaction test; tested, mice sacrificed immediately after social interaction test; control, mice exposed to an empty cage; defeated, mice exposed to an aggressive ICR mouse. decreased, respectively, in the tested defeated group compared Acute administration of desipramine, sertraline, and ari- with those in the tested control group. The NA concentration piprazole did not affect the decrease in time spent in the in the PFC or HIP and the MHPG concentration in the NAc were interaction zone in the second session to expose an unfamil- significantly increased in the nontested defeated and the tested iar ICR mouse when tested 1 day after the last stress exposure control groups, respectively, compared with those of the non- (Figure  3A1–3). When tested 15  days after the last stress expo- tested control group. Lastly, the NA concentration in the HIP was sure, their repeated administration also did not affect body significantly increased in the tested defeated group compared weight gain (data not shown) and the decrease in time spent in with that in the tested control group (Table 1). the interaction zone in the second session (Figure 3B1–3). In the first session of acute administration, there was no significant difference among the groups in the time spent in Effects of Antidepressants and Aripiprazole on the the interaction zone (data not shown), whereas the repeated Impairment of Social Behaviors in Mice Exposed to administration of 20 mg/kg desipramine and 0.003 and 0.01 mg/ Social Defeat Stress as Juveniles kg aripiprazole led to significantly increased time spent in the To investigate the role of monoaminergic neuronal systems in interaction zone in the first session compared with vehicle in the the impairment of social behaviors induced by social defeat defeated group [2-way ANOVA; desipramine: F (1, 70) = 3.62, defeat stress exposure as juveniles, desipramine (10 and 20  mg/kg P = .06; F (2, 70) = 1.11, P = .34; F (1, 70) = 8.53, P < .01, ser- drug defeat × drug i.p.), a NA reuptake inhibitor; sertraline (5 and 10 mg/kg i.p.), a traline: F (1, 60) = 2.00, P = .16; F (2, 60) = 0.28, P = .76; F defeat drug defeat × drug selective 5-HT reuptake inhibitor; and aripiprazole (0.003 and (1, 60) = 7.34, P < .01, aripiprazole: F (1, 96) = 0.66, P = .42; F (2, defeat drug 0.01  mg/kg i.p.), a DA receptor partial agonist, were adminis- 96) = 2.53, P = .09; F (1, 96) = 4.07, P < .05] (data not shown). defeat × drug tered once a day from 1  day after social defeat stress expo- sure for 15 days (Figure 3A). The doses used followed previous Additive Effect of Sertraline with Aripiprazole on the publications; desipramine at 20 mg/kg (p.o.) and sertraline at Impairment of Social Behaviors in Adolescent Mice 10 mg/kg (i.p.) attenuated depressive-like behaviors in a forced Exposed to Social Defeat Stress as Juveniles swim test (Noda et  al., 1997; Mouri et  al., 2012). Aripiprazole at 0.03  mg/kg (p.o.) attenuated phencyclidine-induced the Both clinical and preclinical studies have demonstrated adjunc- impairment of recognition memory (Nagai et  al., 2009); how- tive use of aripiprazole as an augmentation strategy when ever, it did not affect locomotor activity at 0.01  mg/kg (i.p.) combined with SSRIs (Kamei et  al., 2008; Bourin et  al., 2009). (Bourin et al., 2009). The present results shown in Figures 3A1–3 and 3B1–3 indicate Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 842 | International Journal of Neuropsychopharmacology, 2018 Figure  2. Changes in monoamine metabolisms in discrete brain regions of adolescent mice exposed to social defeat stress as juveniles. Changes in serotonin (A), dopamine (B), and noradrenaline (C) utilizations in brain regions of adolescent mice exposed to social defeat stress as juveniles. Data are expressed as a percentage of nontested control group (set at 100%). Each column represents the mean ± SEM (n = 8–9). Other details are shown in Table 1. Two-way ANOVA: (A) F (3, 120) = 2.21, brain region P = .09; F (3, 120) = 19.9, P < .01; F (9, 120) = 1.90, P = .60. (B) F (3, 120) = 1.02, P = .39; F (3, 120) = 7.00, P < .01; F (9, 120) = 0.28, P = .98. (C) group brain region × group brain region group brain region × group F (3, 120) = 6.06, P < .01; F (3, 120) = 2.94, P = .36; F (9, 120) = 1.20 P = .30. *P < .05, **P < .01 vs nontested control group, #P < .05, ##P < .01 vs tested control brain region group brain region × group group (Bonferroni’s test). Nontested: mice sacrificed without the social interaction test, tested: mice sacrificed immediately after social interaction test, control: mice exposed to an empty cage, defeated: mice exposed to an aggressive ICR mouse. exposure to social defeat stress as juveniles leads to the treat- Discussion ment-resistant impairment of social behaviors in adolescents, Adult rodents exposed to social defeat stress repeatedly dis- which is potentially caused by dysfunction of serotonergic and play anxiety- and depressive-like behaviors (Kudryavtseva et al., dopaminergic neuronal systems (Table  1; Figure  2). To investi- 1991; Avgustinovich et al., 2005) such as the impairment of social gate the effect of combined administration of sertraline and ari- behaviors (Berton et al., 2006Tsanko ; va et al., 2006), resembling piprazole on the impairment of social behaviors, we used their the clinical symptoms of stress-related psychiatric disorders. ineffective doses, which were 10 mg/kg and 0.01 mg/kg, respec- In the present study, mice exposed to social defeat stress as tively ( Figure 3A4 and B4). juveniles showed the persistent impairment of social behav- In the second session, acute combined administration of iors in adolescents, which is consistent with our previous find- sertraline with aripiprazole did not affect the impairment of ing (Mouri et al., 2018). The impairment of social behaviors was social behaviors when tested 1 day after the last stress expo- not due to motor dysfunction, since the mice showed no differ - sure, whereas repeated combined administration significantly ence in locomotor activity in the first session of social interac- attenuated it when tested 15 days after that (Figures 3A4 and tion test regardless of their exposure to social defeat stress. The B4). In the first session, however, there was no significant impairment of social behaviors was also replicated even when difference between groups in the time spent in the interac- the C57BL/6J (same strain) mouse was present 1  day after last tion zone when tested at 1 and 15  days after the last stress stress exposure (Mouri et al., 2018). Thus, it is unlikely that the exposure, except for repeated combined administration in the defeated mice did not approach the unfamiliar target ICR mouse defeated group at 15 days [2-way ANOVA; when tested 15 days: only because of the social fear response to the aggressor. On the F (1, 69) = 0.27, P = .60; F (1, 69) = 2.34, P = .13; F (1, Defeat Drug Defeat × Drug other hand, social defeat stress exposure as juveniles did not 69) = 0.16, P = .68, when tested 15 day: F (1, 69) = 1.05, P = .31; Defeat induce pronounced anxiety-like behaviors (Mouri et  al., 2018). F (1, 69) = 2.88, P = .09; F (1, 69) = 3.86, P = .05] (data not Drug Defeat × Drug The immobility in the forced swimming test was enhanced shown). between 1 day and 4 weeks after the last stress, suggesting that Combined administration of sertraline and aripiprazole did vulnerability against intense stress was generated by repeated not affect body weight gain (data not shown) and the explora- exposure to juvenile stress (Mouri et  al., 2018). Therefore, tory activity (supplemental Figure S2). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 843 Figure  3. Effects of antidepressants and aripiprazole on the impairment of social behaviors in adolescent mice exposed to social defeat stress as juveniles. From 1 day after the last stress exposure, the i.p. administration of vehicle (veh), desipramine 10 or 20 mg/kg (A1 and B1), sertraline 5 or 10 mg/kg (A2 and B2), aripiprazole 0.003 or 0.01 mg/kg (A3 and B3) or combined administration of sertraline 10 mg/kg with aripiprazole 0.01 mg/kg (A4 and B4) was started and continued once a day for 15 days. The social interaction test was performed 1 day and 15 days after the last stress exposure. Each column represents the mean ± SEM (n = 8–24). Two-way ANOVA. (A1) F (1, 70) = 94.7, P < .01; F (2, 70) = 1.23, P = .30; F (1, 70) = 0.51, P = .82. (A2) F (1, 60) = 5.28, P < .05; F (2, 60) = 3.30, P < .05; F (1, 60) = 3.77, P = .57. defeat drug defeat × drug defeat drug defeat × drug (A3) F (1, 96) = 33.3, P < .01; F (2, 96) = 3.10, P < .05; F (1, 96) = 0.17, P = .68. (A4) F (1, 69) = 9.83, P < .01; F (1, 69) = 0.95, P = .33; F (1, 69) = 0.57, P = .45. defeat drug defeat × drug defeat drug defeat × drug (B1) F (1, 70) = 13.1, P < .01; F (2, 70) = 1.84, P = .17; F (1, 70) = 0.17, P = .68. (B2) F (1, 60) =4.58, P < .05; F (2, 60) = 1.87, P = .16; F (1, 60) = 1.48, P = .23. (B3) defeat drug defeat × drug defeat drug defeat × drug F (1, 96) = 18.6, P < .01; F (2, 96) = 0.73, P = .49; F (1, 96) = 1.34, P = .25. (B4) F (1, 69) = 6.80, P < .05; F (1, 69) = 0.14, P = .71; F (1, 69) = 10.1, P < .01. ##P < .01 defeat drug defeat × drug defeat drug defeat × drug vs vehicle-administrated control group, †P < .05 vs vehicle-administrated defeated group (Bonferroni’s test). control: mice exposed to an empty cage, defeated: mice exposed to an aggressive ICR mouse. juvenile rodents exposed to social defeat stress repeatedly NAc, HIP, and AMG was decreased in adolescent mice exposed to display depressive-like but not anxiety-like behaviors, and the social defeat stress as juveniles following the social interaction impairment of social behaviors by social defeat stress might be test. Namely, no change in DA metabolism of the tested con- caused by decrease of sociality rather than anxiety to the -tar trol group was observed, while the metabolism was significantly get mouse. In addition, the present stressed mouse model may decreased on social defeat stress exposure in the tested mice be useful as a juvenile stress-based experimental model for the (the tested defeated group) compared with that in the tested study of psychiatric disorders in adolescents. control group. Stress-induced inhibition of DA release in the The detailed mechanisms of social behavioral changes in NAc can explain the impaired defensive reactions under aver - this model have not been elucidated yet. However, it has been sive conditions observed following stressful experiences (Cabib suggested that monoaminergic neuronal systems are impor - and Puglisi-Allegra, 1996). Taken together with these reports tant modulators of the responses to stress (Torres et al., 2002). (Cabib and Puglisi-Allegra, 1996; Firk and Markus, 2007), our Continued or chronic stress exposure is found to have a nega- findings suggest that the not only serotonergic, but also dopa- tive influence on the serotonergic neuronal system and may minergic neuronal systems in adolescent mice are impaired by increase the 5-HT sensitivity or vulnerability as a compensatory social defeat stress exposure as juveniles. There are functional response (Firk and Markus, 2007). In this model, the 5-HT metab- changes associated with the decreased the utilization of 5-HT olism in the PFC and AMG of the nontested control group were and DA, which might be involved in the impairment of social increased following the social interaction test, whereas there behaviors. This could be a model of decreased interest as the were no changes in NA and DA metabolisms. Interestingly, an symptom of depression. increase in the utilization of 5-HT was not observed following The utilization of DA was increased in the PFC and NAc of the social interaction test in mice exposed to the stress. Thus, adolescent mice exposed to social defeat stress (Tanaka et  al., these findings suggest that the serotonergic neuronal dysfunc- 2012). The reason for this discrepancy is unknown but may be tion is involved in the expression of impaired social behaviors. because of difference in aging between samples exposed to social Meanwhile, the utilization of not only 5-HT but also DA in the defeat stress at 3 weeks (juvenile) and 6 weeks (adolescent). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 844 | International Journal of Neuropsychopharmacology, 2018 Prominent developmental transformations are seen in the PFC changes in the utilizations of the 5-HT (P < .05), and DA (P = .08), and limbic regions of the brain of adolescents across a variety NA (P = .06) in the AMG (supplemental Figure S1) but not in other of species; alterations include an apparent shift in the balance brain regions (PFC, NAs, and HIP: data not shown) 15 days after between the mesocortical and mesolimbic dopaminergic neu- the last social defeat stress exposure, indicating monoaminergic ronal system (Spear, 2000). Different development transforma- neuronal dysfunction in the AMG. Multiple functional changes tions in mesocortical and mesolimbic dopaminergic neuronal in the monoaminergic neuronal systems of the AMG occurred systems between juvenile and adolescent mice exposed to over the 15 days and led to persistent impairment of the social social defeat stress may be involved. behaviors in the adolescent mice. Repeated administration Acute or repeated administration of traditional antidepres- of a combination of sertraline and aripiprazole prevented the sants have been shown to be effective in many animal models of development of multiple functional changes in monoaminer- MDD (Caldarone et al., 2015). Repeated administration of parox- gic neuronal systems, leading to reversal of social impairment. etine, which is used widely in humans, attenuated impairment Emotionally related learning, including stress exposure events, of social interaction in adult, defeated mice (Xu et  al., 2018). In is mediated through the interactions of the basolateral HIP and the present study, acute and repeated administration of desipra- AMG formation (Benes, 2010). We reported that the stress expo- mine and sertraline did not attenuate the persistent impairment sure induced the persistent impairment of social behaviors of social behaviors in adolescent mice exposed to social defeat associated with suppression of the hippocampal neurogenesis stress as juveniles. Our findings suggest that exposure to social (Mouri et al., 2018). In the present study, we found the changes defeat stress as juveniles induces an antidepressant-resistant in the utilizations of the 5-HT and DA in the AMG 15 days after impairment of social behaviors in adolescents. Antidepressants the last social defeat stress exposure (supplemental Figure S1). are widely used in the treatment of depression in adolescents, Thus, repeated administration of a combination of sertraline although there are antidepressant-resistant in adolescents and aripiprazole may improve monoaminergic neuronal dys- (Cipriani et  al., 2016). Augmentation pharmacotherapy refers to functions in the HIP and/or AMG 1 and/or 15 days after the stress the addition of drugs that are not standard antidepressants to exposure. Further studies are needed to investigate the effect enhance the effect of a classical antidepressant drug (Carvalho of social defeat stress exposure in monoaminergic neuronal et  al., 2007). Clinically, antidepressant activity of antipsychotics systems of the HIP-AMG pathways and morphological changes, has been observed when administered either alone or in com- such as spine densities and dendritic lengths, during develop- bination with an antidepressant (Kamei et  al., 2008). DA-D and ment of monoaminergic neuronal systems (Lyttle et  al., 2015; D receptor agonists have been tested as augmenting agents in Suri et al., 2015). antidepressant-resistant forms of MDD (Carvalho et  al., 2007). In the present study, there were no significant changes in Aripiprazole is an atypical antipsychotic with a novel pharma- NA metabolism in the all brain regions of the mice exposed to cological profile, acting as a partial DA-D and D receptor ago- social defeat stress when the all groups were compared. Thus, 2 3 nist (Bourin et al., 2009). In the present study, however, acute and it is unlikely that the impairment of social behaviors is due to repeated administration of aripiprazole itself did not attenuate changes in the noradrenergic neuronal system relative to that the persistent impairment of social behaviors in adolescent mice of the controls, although the noradrenergic neuronal system exposed to social defeat stress as juveniles despite the DA hypo- has been explicitly implicated in pathophysiological conditions function observed in the defeated mice. The functional changes induced by the stress exposure (Glavin, 1985). Further, previ- in the utilization of 5-HT and DA were observed in adolescent ous studies have shown that NA transporter-knockout mice mice exposed to social defeat stress as juveniles. These results are resistant to the impairment of social behaviors induced by indicate that multiple functional changes in monoaminergic social defeat stress exposure (Haenisch et al., 2009). It remains neuronal systems are involved in the treatment-resistant impair - unclear whether noradrenergic neuronal systems are involved ment of social behaviors in adolescent mice exposed to social in the treatment-resistant impairment of social behaviors in defeat stress as juveniles. Treatment with a combination of atypi- adolescent mice exposed to social defeat stress as juveniles. The cal antipsychotic drugs and SSRIs had antidepressant effects in mechanisms of additive effect also remain unclear and might patients who did not respond to SSRI monotherapy (Kamei et al., be mediated by multiple receptor properties and other neuronal 2008). Previous studies have indicated that aripiprazole combined systems including the glutamatergic and cholinergic neuronal with inactive doses of antidepressants attenuated depressive-like systems. Aripiprazole acts as not only a partial agonist at the behaviors in a forced swim test (Bourin et al., 2009). At noneffec- DA-D and D receptors but also as a partial agonist at the sero- 2 3 tive doses individually, repeated administration of a combination tonin 5-HT receptors and an antagonist at the serotonin recep- 1A of sertraline and aripiprazole showed additive effects without tors (Bourin et al., 2009). Both monoaminergic and glutamatergic affecting body weight gain and the exploratory activity on the (Sanacora et al., 2012) as well as cholinergic (Mineur et al., 2013) impairment of social behaviors in adolescent mice exposed to neuronal systems have driven the research on the impairment social defeat stress as juveniles in the present study. Thus, the of social behaviors induced by social defeat stress exposure. The combined administration of sertraline with aripiprazole may be additive effect may be mediated, at least partly, by the activation useful as a new treatment strategy for treatment-resistant of of the serotonergic and dopaminergic neuronal systems. Further stress stress-related psychiatric disorders. studies are needed to investigate the complex mechanisms It is unclear why repeated but not acute administration of behind the functional changes in both the noradrenergic and a combination of sertraline and aripiprazole attenuates the serotonergic/dopaminergic neuronal systems, including recep- impairment of social behaviors induced by social defeat stress tor functions and other neuronal systems, leading to the devel- exposure as juveniles, whereas the serotonergic and dopa- opment of treatment-resistant impairment of social behaviors. minergic neuronal systems were impaired 1  day after the last Aripiprazole is a dopaminergic neuronal system stabilizer; exposure to social defeat stress. There are only a few clinical namely, a drug that can enhance dopaminergic neuronal activity or preclinical studies that have assessed the effects of chronic when it is diminished or suppress it when it is increased (Stahl, administration of aripiprazole in combination with antidepres- 2001a, 2001b). Bourin et  al. (2009) referred that the combina- sants in adolescent depressed patients or in mice. We found tion of aripiprazole and selective serotonin reuptake inhibitors Downloaded from https://academic.oup.com/ijnp/article-abstract/21/9/837/4956098 by Ed 'DeepDyve' Gillespie user on 04 September 2018 Hasegawa et al. | 845 (SSRIs) in outpatients with depression who did not experience Avgustinovich DF, Kovalenko IL, Kudryavtseva NN (2005) A model significant clinical improvement after taking antidepressants of anxious depression: persistence of behavioral pathology. alone was performed in clinical trials (Papakostas et  al., 2004; Neurosci Behav Physiol 35:917–924. Simon and Nemeroff, 2005; Marcus et al., 2008). These findings Benes FM (2010) Amygdalocortical circuitry in schizophre- suggest that aripiprazole adjunction could be used as an aug- nia: from circuits to molecules. Neuropsychopharmacology mentation strategy when combined with SSRIs (Bourin et  al., 35:239–257. 2009). Bourin et  al (2009) demonstrated that combined admin- Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo istration of subactive doses of antidepressants (which activate SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia the serotonergic system) with aripiprazole (which activates the LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the dopaminergic system) induced an antidepressive-like effect in a mesolimbic dopamine pathway in social defeat stress. mouse model of depression. Thus, we speculated that aripipra- Science 311:864–868. zole may work as an agonistic rather than antagonistic for dopa- Bourin M, Chenu F, Prica C, Hascoët M (2009) Augmentation mine-D receptor in the present experiment. effect of combination therapy of aripiprazole and antidepres- In conclusion, exposure to social defeat stress as juveniles sants on forced swimming test in mice. Psychopharmacology induces the treatment-resistant impairment of social behaviors (Berl) 206:97–107. in adolescents through the functional changes in the seroton- Boyarskikh UA, Bondar NP, Filipenko ML, Kudryavtseva NN (2013) ergic and dopaminergic neuronal systems. Administration of a Downregulation of serotonergic gene expression in the Raphe combination of sertraline and aripiprazole may be useful as a nuclei of the midbrain under chronic social defeat stress in new treatment strategy in adolescents, who had been exposed male mice. Mol Neurobiol 48:13–21. to adverse juvenile experiences, with treatment-resistant Cabib S, Puglisi-Allegra S (1996) Stress, depression and the stress-related psychiatric disorders. mesolimbic dopamine system. Psychopharmacology (Berl) 128:331–342. Caldarone BJ, Zachariou V, King SL (2015) Rodent models of treat- Funding ment-resistant depression. Eur J Pharmacol 753:51–65. This study was supported by Grants-in-Aid for Scientific rd Cao JL, Covington HE 3 , Friedman AK, Wilkinson MB, Walsh Research C (grant nos. 24590219, 26460240, 16K08421), B (grant no. JJ, Cooper DC, Nestler EJ, Han MH (2010) Mesolimbic dopa- 17H04252), and the private University Research Project from the mine neurons in the brain reward circuit mediate suscepti- Ministry of Education, Culture, Sports, Science and Technology bility to social defeat and antidepressant action. J Neurosci (MEXT) of Japan, Grant-in-Aid for the Strategic Research Program 30:16453–16458. for Brain Sciences from Japan Agency for Medical Research and Carvalho AF, Cavalcante JL, Castelo MS, Lima MC (2007) development, AMED, The Adaptable and Seamless Technology Augmentation strategies for treatment-resistant depression: Transfer Program Through Target-driven R&D, Japan Science and a literature review. J Clin Pharm Ther 32:415–428. Technology Agency (grant no. AS251Z03018), Meijo University Chen P, Fan Y, Li Y, Sun Z, Bissette G, Zhu MY (2012) Chronic Research Institute grant, and Smoking Research Foundation social defeat up-regulates expression of norepinephrine Grant for Biomedical Research. transporter in rat brains. Neurochem Int 60:9–20. Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, Coghill D, Zhang Y, Hazell P, Leucht S, Cuijpers P, Pu J, Cohen Acknowledgments D, Ravindran AV, Liu Y, Michael KD, Yang L, Liu L, Xie P (2016) We thank Mayu Ukai, Masayuki Taniguchi, and all staff members Comparative efficacy and tolerability of antidepressants for of Faculty of Pharmacy, Meijo University that were involved in major depressive disorder in children and adolescents: a net- this study. work meta-analysis. Lancet 388:881–890. Firk C, Markus CR (2007) Review: serotonin by stress interaction: a susceptibility factor for the development of depression? Statement of Interest J Psychopharmacol 21:538–544. Dr. Norio Ozaki has received research support or speak- Flügge G (2000) Regulation of monoamine receptors in the brain: ers’ honoraria from, or has served as a consultant to Astellas, dynamic changes during stress. Int Rev Cytol 195:145–213. 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