Background: Patients with post-traumatic stress disorder frequently report persistent problems with social interactions, emerging after a traumatic experience. Chronic social defeat stress is a widely used rodent model of stress that produces robust and sustained social avoidance behavior. The avoidance of other rodents can be reversed by 28 days of treatment with selective serotonin reuptake inhibitors, the only pharmaceutical class approved by the U.S. Food and Drug Administration for treating post-traumatic stress disorder. In this study, the sensitivity of social interaction deficits evoked by 10 days of chronic social defeat stress to prospective treatments for post-traumatic stress disorder was examined. Methods: The effects of acute and repeated treatment with a low dose of buprenorphine (0.25 mg/kg/d) on social interaction deficits in male C57BL/6 mice by chronic social defeat stress were studied. Another cohort of mice was used to determine the effects of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg/d), the NMDA antagonist ketamine (10 mg/kg/d), and the selective kappa opioid receptor antagonist CERC-501 (1 mg/kg/d). Changes in mRNA expression of Oprm1 and Oprk1 were assessed in a separate cohort. Results: Buprenorphine significantly reversed social interaction deficits produced by chronic social defeat stress following 7 days of administration, but not after acute injection. Treatment with fluoxetine for 7 days, but not 24 hours, also reinstated social interaction behavior in mice that were susceptible to chronic social defeat. In contrast, CERC-501 and ketamine failed to reverse social avoidance. Gene expression analysis found: (1) Oprm1 mRNA expression was reduced in the hippocampus and increased in the frontal cortex of susceptible mice and (2) Oprk1 mRNA expression was reduced in the amygdala and increased in the frontal cortex of susceptible mice compared to non-stressed controls and stress-resilient mice. Conclusions: Short-term treatment with buprenorphine and fluoxetine normalized social interaction after chronic social defeat stress. In concert with the changes in opioid receptor expression produced by chronic social defeat stress, we speculate that buprenorphine’s efficacy in this model of post-traumatic stress disorder may be associated with the ability of this compound to engage multiple opioid receptors. Keywords: PTSD, buprenorphine, fluoxetine, CERC-501, ketamine, chronic social defeat stress, social interaction Introduction Emotional numbing and social deficits are frequently observed (Hames et al., 2013; Air et al., 2015 ), such as posttraumatic stress in patients diagnosed with stress-related psychiatric disorders disorder (PTSD) (Cisler et al., 2015 ; Dutton et al., 2016 ; LaMotte Received: July 12, 2017; Revised: August 17, 2017; Accepted: August 22, 2017 Published by Oxford University Press on behalf of CINP 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US. This Open Access article contains public sector information licensed under the Open Government Licence v2.0 (http://www.nationalarchives.gov.uk/doc/ open-government-licence/version/2/). 164 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Browne et al. | 165 Significance Statement Post-traumatic stress disorder (PTSD) develops after exposure to a serious threatening event and involves significant, persistent negative changes in mood, arousal, and cognition. Social detachment and lingering social impairment often begin or worsen after the traumatic event. There is a significant medical need to develop better, more effective medications for PTSD. The studies presented here examined the effects of 3 potential new medications for PTSD in mice after chronic social defeat, a rodent model of psychosocial stress that causes enduring social avoidance behavior. The mixed opioid agonist/antagonist buprenorphine, the NMDA receptor antagonist ketamine, and the selective kappa opioid receptor antagonist CERC-501 were studied for the rapid reversal of social interaction deficits induced by chronic social defeat and compared with the SSRI fluoxetine, an approved ther - a peutic class for PTSD. In this paper, we show that both fluoxetine and buprenorphine reversed the social interaction deficits following 1 week of treatment. Ketamine or CERC-501 did not alter the behaviors induced by defeat. Overall, these data support further investigation of buprenorphine, and its underlying mechanisms, as a potential therapeutic for PTSD. et al., 2016 ; Renshaw and Campbell, 2016; Venta et al., 2016 ). ability of buprenorphine to reverse social interaction deficits fol - Triggered by exposure to an actual or perceived life-threatening lowing chronic social defeat stress (CSDS) in mice. CSDS is a well- event, serious injury, or sexual violence, PTSD is a debilitating established preclinical model of stress that produces pronounced mental health disorder ( Goldstein et al., 2016 ), with a current life - and persistent deficits in social interaction that are long-lasting time prevalence of 3.6% in men and 9.7% in women in the United and sensitive to chronic administration of antidepressant drugs States (Breslau, 2009). Although behavioral and pharmacological (Berton et al., 2006 ; Nikulina et al., 2008 ; Golden et al., 2011 ). Opioid therapies (e.g., selective serotonin reuptake inhibitor [SSRIs]) are involvement in CSDS has been supported by reports of region- available, they are not effective for most patients. As many as 50% specific increases in mRNA expression of Oprm1 (Nikulina et al., of patients are treatment resistant, suffering from chronic unr - e 2008) and DYN concentrations ( Berube et al., 2013 ). Upregulated mitted PTSD for years (Green et al., 2006 ; Ravindran and Stein, DYN signaling has been proposed as a key mediator of the beha- v 2009; Choi et al., 2010 ; Bryant et al., 2013 ). Thus, new pharmaco- ioral deficits induced following CSDS exposure ( McLaughlin et al., therapies are urgently needed to alleviate the symptoms of PTSD. 2006). Therefore, we anticipated that compounds that modulate Modulation of the endogenous opioid system presents a opioidergic tone may have beneficial effects in altering social potential opportunity for developing novel therapeutics for exploration in this model of stress, which is proposed to be a PTSD. Endogenous κ- (KOR) and μ- (MOR) opioid receptors are behavior endpoint that is relevant to PTSD ( Flandreau and Toth, critical regulators of mood ( Lutz and Kieffer, 2013; Mechling et 2017). Focusing on the development of rapid treatment effects, al., 2016). In response to stressful stimuli, binding of KORs by the mice were tested following acute (24 hours following a single endogenous opioid dynorphin (DYN) produces dysphoria, aver - injection) and repeated treatment (once daily for 7 days). sion, and negative affect ( Land et al., 2008 ; Knoll and Carlezon, A follow-up study compared the effects of buprenorphine 2010). Conversely, activation of MORs is necessary for social with those of the SSRI fluoxetine, the analgesic/anesthetic reward (Trezza et al., 2011 ; Hsu et al., 2013 ; Resendez et al., ketamine, and the selective KOR antagonist CERC-501 (formerly 2013) and reinforcement of the rewarding properties of drugs LY2456302). There was a clear rationale for choosing each one of abuse (Charbogne et al., 2014 ). Recent clinical reports have of these comparator compounds. Because fluoxetine had only highlighted the potential therapeutic impact of opioids in PTSD; been tested in CSDS following 28 days of treatment ( Berton morphine administered during early resuscitation and trauma et al, 2006) and SSRIs are the only class of drugs currently care was associated with reduced risk of a subsequent PTSD approved by the FDA for PTSD, it would be informative to exam - diagnosis after serious injury Holbr ( ook et al., 2010 ). Similarly, ine the effects of an SSRI on social deficits in a rapid time frame a small study noted that the mixed opioid analgesic buprenor - like that of buprenorphine. Second, ketamine was included phine alleviated PTSD symptomology in patients diagnosed as a comparator, because recent clinical studies have demon - with comorbid chronic pain and PTSD ( Seal et al., 2016 ). strated rapid reductions in symptom severity following keta - Buprenorphine is a MOR partial agonist and KOR antagonist mine infusion in patients with treatment-resistant depression that is currently approved by the FDA for the treatment of opi - (Zarate et al., 2006 ; Aan Het Rot et al., 2010 ; DiazGranados et al., oid addiction at high doses and for chronic pain at lower doses. 2010; Ibrahim et al., 2011; Murrough et al., 2013 ; Ionescu et al., Compelling clinical evidence has demonstrated the potential 2016) and possibly in patients with chronic PTSD ( Feder et al., of low doses of buprenorphine to rapidly alleviate depressive 2014). Finally, as KORs have been implicated in the emergence symptoms in treatment-resistant depressed patients ( Bodkin et of affective behaviors following CSDS ( McLaughlin et al., 2006 ) al., 1995; Nyhuis et al., 2008 ; Ehrich et al., 2014 ; Karp et al., 2014 ). and buprenorphine’s antidepressant-like effects are known to Furthermore, buprenorphine produced marked reductions in involve KORs (Falcon et al., 2016), the selective KOR antagonist suicidal ideation (Striebel and Kalapatapu, 2014 ; Yovell et al., CERC-501 was expected to provide valuable information regar - d 2016). In parallel with these clinical findings, preclinical e -vi ing the therapeutic potential of this class of compounds in the dence from our laboratory has shown that low-dose buprenor - treatment of PTSD. phine is highly effective across a range of behavioral tests relevant to anxiety and depression in mice and rats ( Browne et Methods al., 2015; Falcon et al., 2015 ; Robinson et al., 2016 ; Browne et al., 2017). Moreover, we have shown that buprenorphine effectively Animals reversed stress-induced anhedonia, anxiety, and depressive-like behavior in mice following exposure to unpredictable chronic Male C57BL/6J mice, age 8 to 9 weeks, and retired breeder mild stress within 1 week of treatment ( Falcon et al., 2016 ). CD-1 mice 4 to 6 months of age were obtained from Jackson Given the compelling support for buprenorphine’s anti-stress Laboratories and allowed 1 week to adjust to the vivarium prior effects, the studies presented here originated by investigating the to the onset on behavioral experiments. Mice were maintained Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 166 | International Journal of Neuropsychopharmacology, 2018 under a 12-h-light/-dark cycle (lights on at 7:30 am) in tempera- as the “interaction zone”. Each mouse was allowed to freely ture- and humidity-controlled rooms. Food and water were pr - o explore the arena for 150 seconds in the absence of a conspe - vided ad libitum. The first cohort of mice was used to assess the cific target mouse. The mice were returned to their home cage effect of buprenorphine treatment on CSDS-induced social defi- briefly for ~1 minute, during which time the experimenter intro- cits. Following this study, another cohort was used to establish duced the target CD-1 mouse into the wire-mesh cage at the the optimal dose of CERC-501 and ketamine for the subsequent end of the box. The second 150-second session started immedi- CSDS study conducted in an additional cohort. Gene expression ately. Using a video-tracking system, the time spent interacting analysis was performed using tissue obtained from a separate with the unfamiliar target mouse was recorded. Social inter - cohort of mice exposed to the CSDS procedure. All studies were action ratios were determined as: time in interaction zone with approved by the Institutional Animal Care and Use Committee mouse / time in interaction zone without mouse. The perform- for the University of Pennsylvania and conducted in accor -d ance of defeated mice was split into 2 categories: susceptible ance with the PHS Policy on Humane Care and Use of Laboratory mice exhibit pronounced social avoidance (interaction ratios <1) Animals. and resilient mice that sustained social interaction (interaction ratios >1). For these studies, drug treatments were evaluated in sus - Drugs ceptible mice only. For the buprenorphine study, 50 mice were Buprenorphine hydrochloride (0.25 mg/kg; RTI, National exposed to the social defeat procedure, and 2 were excluded Institute on Drug Abuse), fluoxetine hydrochloride (10 mg/kg; due to wounding; 42% were resilient and 58% were susceptible AK Scientific), ketamine (Ketaset), and CERC-501 (formerly from a total of 48 mice. For the second experiment, 80 mice LY2456302; Eli Lily) were prepared freshly on the morning of were exposed to the CSDS procedure and 6 were excluded due each experimental day and administered i.p. using a 10-mL/kg to wounding. Of the remaining 74 mice, 48% were resilient and injection volume. Fluoxetine and buprenorphine were dissolved 52% were susceptible. Mice were retested in the same apparatus in water (sterile HPLC grade water, MilliQ system, Millipore); on the first day after the cessation of the social defeat paradigm ketamine was dissolved in 0.9% sterile saline (Hospira Inc.), and (baseline) and then again 24 hours following drug administr - a CERC-501 in vehicle (sterile water, 1% lactic acid [85%], sonicated tion on day 1 and day 7 of treatment. for 5 minutes and titrated to pH 5). Mice in the nonstress control groups received 0.9% saline injections. Drugs were administered Selection of Doses for the CSDS Study on the day following the first baseline social interaction test, and mice were then testing 24 hours after drug treatment on day 1 The doses of ketamine and CERC-501 used in the CSDS model and day 7. Prior to the CSDS study, dose-response curves were were selected based on 2 behavioral screens for antidepressant determined for ketamine and CERC-501 in the forced swim test activity: the FST and the NIH tests. We have previously shown (FST) and novelty-induced hypophagia (NIH) test to determine that the 0.25-mg/kg buprenorphine dose was active in both the an appropriate behaviorally active dose 24 hours post injection FST and NIH test and could be injected in mice chronically with - for use in the CSDS study. out causing toxicity ( Falcon et al., 2015 , 2016; Robinson et al., 2016). Similarly, the selected 10-mg/kg/d dose of fluoxetine was previously shown to reduce immobility in the FST ( Lucki et al., CSDS 2001), reduce approach latency in the NIH test Hodes et ( al., 2010 ), The CSDS studies were conducted according to a previously and bind to SERT in brain and was administered to C57BL/6 mice established protocol ( Berton et al., 2006 ) with defeat bouts last - chronically without development of toxicity ( Hirano et al., 2005 ; ing 5 minutes. Resident CD-1 mice were prescreened for aggres - Balu et al., 2009 ). As we did not have prior experience with CERC- sion and housed 1 per cage in hamster cages (26.7 x 48.3 x 15.2 501 and ketamine, we conducted dose-response curves for these cm) with a Plexiglas perforated divider. C57BL/6J mice were ini - compounds to identify comparable behaviorally active doses on tially housed 5 per cage until the beginning of the stress par - a these tests. digm. For 10 consecutive days, each C57BL/6J mouse was placed into the cage of a different resident CD-1 mouse for 5 minutes, FST where they engaged in aggressive physical contact. Once the defeat bout was over, the intruder C57BL/6J was transferred to The FST was conducted in our laboratory as described pre-vi the other side of a cage divider for the remainder of the 24-hour ously (Lucki et al., 2001 ; Balu et al., 2009 ; Falcon et al., 2015 ). Mice period, allowing the mice to see, smell, and hear but not touch were gently placed in a cylinder of water (21 cm in diameter), one another. This continuous sensory interaction comprises the filled with 15 cm of water (25°C ± 1°C), for 6 minutes. Water was psychological component of the stressor, as the C57BL/6J mouse changed between each animal. A rater blind to the treatment was unable to escape the presence of the aggressor. Nonstressed conditions evaluated the full 6 minutes of the test from video control mice did not experience social defeat. They were housed recordings, as C57BL/6J mice develop immobility during the first in pairs in the same experimental cages (including divider) and 2 minutes of this test. The data are presented as immobility(s). were handled daily. Following the cessation of the CSDS expos - Drugs were administered 24 hours prior to testing. ure, mice were housed in pairs as per control animals. NIH Social Interaction Test The NIH test measures approach latencies of rodents for palat - Social approach behaviors of susceptible and control mice able food in a novel arena. Approach latencies in the NIH test were tested following CSDS in a social interaction open-field are diminished following acute administration of anxiolytics arena (42 cm × 42 cm × 42 cm), in which a wire-mesh cage was or chronic administration of antidepressants ( Dulawa and Hen, placed at the end of the arena ( Challis et al., 2013 ). An area of 2005). Mice were trained to rapidly approach and readily con - 14 cm × 24 cm surrounding the wire mesh cage was designated sume a palatable food (3 peanut butter chips in a clear petri Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Browne et al. | 167 dish) as described previously (Balu et al., 2009 ; Falcon et al., 2015). Daily training sessions were performed until mice met the criteria of 3 consecutive days with approach latencies of ≤30 seconds. Testing in the novel arena was conducted in a different room from that of training. On the test day, mice were placed in a clear polycarbonate cage (25.5 × 46 × 20 cm) that was brightly lit (800 Lux) and scented with lemon (20% Lemon Joy solution). Latency, defined as the time to approach and start consuming the peanut butter chips located in the dish in the center of the arena, was scored for each mouse. The 15-minute test session duration was recorded with a digital camera. Quantitative RT-PCR Brain tissue from the frontal cortex (FC), hippocampus (Hp), striatum (Str), and amygdala (Amy) was collected by gross dis - section from non-stressed (NS) controls, stress resilient and stress susceptible male C57BL/6J mice. Briefly, a TriZol (cat. no. Figure 1. Buprenorphine reversed social interaction deficits in susceptible mice. 15596-026, Ambion, ThermoFisher Scientific) chloroform-based Across the 3 testing exposures, non-stressed (NS) mice spent a greater amount extraction method was used to isolate total RNA. Samples were of time interacting with the target mouse compared with susceptible CSDS mice homogenized using a Kontes Pellet Pestle. Quantification of (***P < .001, **P < .01). Social interaction scores of susceptible CSDS mice were nor - the isolated RNA was performed using the NanoDrop spectr -o malized following 7 days of treatment with buprenorphine compared with mice treated with saline (& P < .05). photometer and ND-1000 software (Thermo Fisher Scientific) at the optical densities of 260 and 280 nm. Samples with poor RNA quality/degradation were excluded at this stage. Reverse control groups that received treatment with buprenorphine or transcriptase amplification of cDNA from total RNA was per - saline. Group sizes were n = 9 for both control groups, n = 13 for formed using the High-Capacity RNA-to-cDNA Kit (Applied susceptible saline, and n = 15 for susceptible buprenorphine. Biosystems, ThermoFisher Scientific) conducted using a MJ, Test-retest conditions did not induce alterations in the Research PTC-100 thermal cycler. Taqman Gene Expression social interaction values in untreated control and susceptible Assays (Applied Biosystems, ThermoFisher Scientific) were used mice. A significant stress*treatment interaction was observed in a CFX96 Touch Real-Time PCR Detection System (BioRad) to on social interaction (F = 2.321, P = .04). Tukey’s multiple com- 6, 84 quantify the following target genes during amplification: Oprk1 parisons tests determined that susceptible mice exhibited lower Mm01230885_m1, Oprm1 Mm01188089_m1, and the endogenous social interaction values than the corresponding control groups control Rn18S Mm04277571_s1. For each sample, the average of at baseline ( P < .001), day 1 (P < .001), and day 7 (P < .01). CSDS- the triplicate cycle numbers at threshold crossing (CT) value for stressed mice treated with buprenorphine did not show changes the endogenous control was subtracted from the average CT v -al in social interaction scores 24 hours after a single injection. ues for the target gene, generating ΔCT values. As the PCR effi - However, these mice exhibited significantly higher interaction ciencies for both the endogenous control gene and target gene scores compared with saline-treated controls following 7 days were equal (~1), the changes in expression of the target gene of treatment with buprenorphine ( P < .05). were expressed as 2-ΔΔCT for each sample calculated. All data were normalized to the control/saline group and expressed as Dose Response Curves for CERC-501 and Ketamine fold change for statistical analysis and presentation. in the NIH Test and the FST To establish the optimal dose of CERC-501 and ketamine for Statistical Analysis repeated treatment in the CSDS model, dose-response curves Data are expressed as mean ± SEM. Statistical analysis was were determined on two behavioral tests used to screen com - performed using GraphPad Prism version 7.00 for Windows pounds for antidepressant-like activity: the NIH test and the (GraphPad Software). One-way ANOVAs with Dunnett’s mul - FST. tiple comparisons were used to evaluate the effects of CERC-501 and ketamine in the FST and NIH, and to determine any CSDS- FST induced alterations in gene expression. Two-way repeated- A significant effect of treatment with CERC-501 was observed on measures ANOVA were used to evaluate a treatment*stress immobility scores (F = 4.775 P < .007; n = 9–10/group) (Figure 2a). 3, 34 interaction on social interaction scores. Bonferroni multiple More specifically, mice displayed reductions in the time spent comparisons tests were used where appropriate. immobile following administration of CERC-501 at doses of 1 (P < .05) and 3 mg/kg ( P < .01). A similar effect of ketamine treat - ment was detected for immobility (F = 5.138, P < .007; n = 7–8/ 3, 26 Results group) (Figure 2c). All the doses tested effectively reduced the time spent immobile [1 ( P < .05), 3 (P < .05), and 10 mg/kg ( P < .01)] Buprenorphine Reversed CSDS-Induced Social compared with the vehicle-treated control group. Interaction Deficits Social interaction was measured after exposure to 10 sessions of NIH CSDS (baseline) and again after acute (1 day) and repeated treat - Approach latency in the NIH was significantly altered follo -w ment (7 days) with buprenorphine or saline ( Figure 1). Behavioral ing CERC-501 treatment (F = 3.668, P < .05; n = 9–10/group) 3, 35 scores after drug treatment were compared with nonstress (Figure 2b ). Multiple comparisons revealed that CERC-501 (3 mg/kg) Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 168 | International Journal of Neuropsychopharmacology, 2018 Figure 2. Acute behavioral effects of ketamine and CERC-501 tested at 24 hours post injection. In the FST, immobility time was reduced significantly following adminis - tration of 1 ( P < .05) and 3 mg/kg ( P < .01) of CERC-501 (Figure 2a). Additionally, ketamine treatment significantly reduced the time spent immobile at all doses [1 ( P < .05), 3 (P < .05), and 10 mg/kg ( P < .01)] compared with vehicle (Figure 2c). In the NIH test, mice treated with CERC-501 (3 mg/kg) significantly decreased latencies to approach and consume food compared with vehicle (P < .01) (Figure 2b). Similarly, ketamine (10 mg/kg) significantly decreased approach latencies compared with vehicle-treated controls in the NIH test ( Figure 2d). significantly decreased latencies to consume the peanut but - (84.51 seconds ± 6.97). A significant stress*treatment interac - ter chips compared with the vehicle-treated group ( P < .05). tion was noted on social interaction scores of susceptible mice A trend towards decreased approach latencies was observed (F = 3.573, P = .005; n = 6–8/group). None of the drugs produced 6,52 for the 1-mg/kg dose (P = .07). Ketamine also produced a signifi - a notable change in social interaction following a single drug cant reduction of latency values (F = 3.212, P < .04; n = 12–15/ treatment. However, on day 7, there was a significant increase 3, 51 group) (Figure 2d). Only the highest dose of ketamine (10 mg/kg) in social interaction scores in mice treated with fluoxetine com - decreased the latencies of mice to approach and begin eating pared with their corresponding baseline scores ( P < .001). No the food in the novel cage ( P < .05). effect of treatment with ketamine or CERC-501 was observed. Social Avoidance Was Reversed by Fluoxetine, but Oprm1 and Oprk1 Expression in Limbic and Cortical Not Ketamine, or CERC-501 Regions of Susceptible Mice Based on the results of the acute behavioral tests, the doses of The most potent effects of buprenorphine are as a MOR partial CERC-501 (1 mg/kg) and ketamine (10 mg/kg) were chosen for agonist and KOR antagonist ( Cowan, 2007), and we previously the CSDS study. The dose of fluoxetine (10 mg/kg) was selected noted the reversal of stress-induced alterations in opioid rece - p based on previous studies conducted in our laboratory ( Lucki tor mRNA expression post buprenorphine ( Falcon et al., 2016 ). et al., 2001 ; Hodes et al., 2010) and the published relationship We hypothesized that the ability of buprenorphine but not between plasma concentrations of fluoxetine and SERT binding CERC-501 to produce beneficial behavioral changes in the CSDS in mouse brain ( Hirano et al. 2005 ). model was due to buprenorphine’s capacity to modulate MORs No significant interaction or main effect of stress or treat - in addition to blockade of KORs. To determine whether MORs ment was observed on social interaction scores of control mice and KORs were equally altered in the CSDS model, a separate across the test days ( Figure 3a; n = 6–8/group). CSDS produced cohort of mice exposed to the CSDS procedure was used to significant reductions in social interaction of susceptible mice evaluate Oprm1 and Oprk1 gene expression in nonstressed con- at baseline, showing mean interaction values (22.31 seconds trol, susceptible, and resilient mice. This cohort consisted of 40% ± 5.92) (Figure 3b) that were nearly 4-fold lower than controls resilient mice and 60% susceptible mice (n = 5–8/group). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Browne et al. | 169 Discussion These experiments examined the ability of buprenorphine, and a series of related compounds, to reverse social interaction deficits in susceptible mice following CSDS. CSDS is a well- established preclinical model of stress that produces distinctive behavioral deficits. In the initial study, repeated treatment with buprenorphine was demonstrated to reverse the social inter - action deficits that are characteristic of CSDS without altering social interaction in nonstressed control mice. A follow-up study evaluated the effects of fluoxetine, ketamine, and the select - ive KOR antagonist CERC-501 for comparison. Chronic admin - istration of fluoxetine reversed the deficits produced by CSDS, whereas chronic administration of ketamine and CERC-501 were ineffective. Recent studies by our laboratory and others have shown that buprenorphine produces behavioral changes in numerous tests in rodents that are associated with the effects of antidepressant and anxiolytic drugs in humans. In addition, using unpredict - able chronic mild stress as a model of depression, buprenor - phine produced reversal of behavioral deficits in anhedonia, stress coping, and anxiety with repeated treatment for 1 week (Falcon et al., 2016 ). Our data parallel the reduced responses to stress and subjective level of threat ( Bershad et al., 2015 ) and decreased responses to negative social stimuli while enhanc - ing positive responses to social stimuli ( Bershad et al., 2016 ) produced by buprenorphine in healthy volunteers exposed to psychosocial stress challenges. These results are noteworthy, because they correspond with the results from clinical evalu - ation of buprenorphine in numerous studies in depressed patients ( Karp et al., 2014 ; Yovell et al., 2016 ; Stanciu et al., 2017 ). Furthermore, ALKS-5461, a combination of buprenorphine and the mu opioid receptor antagonist samidorphan, also induced Figure 3. Social interaction deficits in susceptible mice were reversed by fluox - positive effects within 1 week of treatment for treatment-resist - etine. Non-stress mice did not exhibit any significant differences in the amount ant depression (Ehrich et al., 2014 ). of time in the interaction zone over the course of the experiment ( Figure 3a). Susceptible mice exhibited less time interacting with the conspecific target on Fluoxetine and imipramine were shown previously to ameli - all 3 test days compared with control mice ( Figure 3b). Following 7 days but not orate CSDS-induced social avoidance following chronic (28 days), 24 hours of treatment with fluoxetine (10 mg/kg), social interaction scores of but not after acute (1 day), administration and this suggested susceptible C57BL/6J mice were restored to a level comparable with control mice that long-term treatment with antidepressant drugs was neces - (***P < .001 compared with baseline values). No effect was observed with keta - sary to impact social behavior ( Berton et al., 2006 ; Tsankova et mine (10 mg/kg) or CERC-501 (1 mg/kg) treatment. al., 2006). Although somewhat unexpected, the present results indicate that 1 week of fluoxetine treatment was sufficient for A significant effect of stress was detected for Oprm1 mRNA improving social avoidance scores following CSDS. To our kno- w expression in the HP (F = 3.672, P = .047; Figure 4a), where ledge, 1 week of fluoxetine treatment has not been examined in 2,17 resilient mice exhibited lower levels of expression compared previous studies applying the CSDS protocol. These data suggest with controls ( P < .05). Susceptible mice also exhibited a non - that both buprenorphine and fluoxetine can modulate social significant decrease in Oprm1 mRNA levels in this region. No deficits within a relatively short period. Although buprenor - significant effect of stress was distinguished for Oprk1 expres- phine and fluoxetine produced comparable amelioration of the sion in the Hp (Figure 4b). In the Amy, only a trend towards a negative outcomes of the CSDS, buprenorphine may produce its stress effect was noted for Oprm1 mRNA expression ( Figure 4c), effects through mechanisms that are distinct from SSRIs. The whereas Oprk1 mRNA expression was dramatically altered by SSRIs sertraline and paroxetine are treatments approved by the stress in this region (F = 7.28, P = .008; Figure 4d). Tukey mul - FDA for PTSD, and a recent meta-analysis established an overall 2, 12 tiple comparison tests detected a decrease in amygdalar Oprk1 “small positive impact” for fluoxetine, paroxetine, and venlafax - mRNA expression in susceptible mice that was significantly ine on PTSD symptoms ( Hoskins et al., 2015 ). Repeated exposure lower than both control and resilient mice ( P < .05). Although no to CSDS induced social avoidance in mice, a behavioral change significant changes in gene expression were apparent in the Str that resembles one of the key symptoms of PTSD (Flandreau (Figure 4e, f), robust alterations in the expression of both genes and Toth, 2017). Therefore, the similar effects obtained between were detected in the FC. Cortical Oprm1 mRNA was significantly buprenorphine and fluoxetine could be viewed as supporting an altered by stress (F = 6.486, P = .008; Figure 4g), where the levels extension of indications for buprenorphine for the treatment of 2,16 of Oprm1 in resilient mice were considerably lower than those PTSD. measured in susceptible animals ( P < .01). Similarly, a main effect KOR blockade has been associated with anti-stress effects of stress was observed for Oprk1 in the FC (F = 4.233, P = .037) (Carlezon and Krystal, 2016 ) and could underlie some of 2, 14 (Figure 4h). Multiple comparisons test revealed that the ele -va buprenorphine’s ability to alleviate negative affect and anhe - tion in Oprk1 mRNA expression in susceptible mice was higher donia (Falcon et al., 2015 , 2016; Robinson et al., 2016 ; Browne than the levels determined in resilient and control mice ( P < .05). et al., 2017). The selective KOR antagonist CERC-501 was Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 170 | International Journal of Neuropsychopharmacology, 2018 Figure 4. This panel of graphs depicts the changes in gene expression of Oprm1 (a–d) and Oprk1 (e–h) in the hippocampus (HP), amygdala (Amy), striatum (Str), and frontal cortex (FC) of nonstressed control, susceptible, and resilient mice P <. .*05 between control and susceptible mice, & P < .05 between control and resilient; P# < .05, ##P < .01 for difference between susceptible and resilient mice. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Browne et al. | 171 examined, anticipating that it might produce many similar our laboratory has recently demonstrated that the effect of effects to buprenorphine. Accordingly, CERC-501 produced clear buprenorphine in the NIH test is mediated by functional bloc - k behavioral effects in the FST and NIH tests, behavioral assays ade of MORs (Robinson et al., 2016 ). Together, these findings sug - in mice that are also sensitive to many antidepressant drugs gest that the development of compounds with a combination of (Lucki et al., 2001 ; Dulawa and Hen, 2005). Others have shown MOR and KOR blockade, as achieved by buprenorphine, should that CERC-501 produces robust behavioral effects in tests r - el be considered as providing a beneficial therapeutic profile for evant to motivation, affect, and addiction in both humans and stress-related disorders such as PTSD. rodents (Rorick-Kehn et al., 2014 , 2015; Jackson et al., 2015 ). As As buprenorphine, but not CERC-501 or ketamine at the CERC-501 produced significant effects in the NIH test following doses used in this study, reversed the social interaction defi - a single injection, these actions appeared like those produced by cits induced by CSDS, we hypothesized that the contribution other rapid-acting clinical therapeutics, like ketamine. Despite of opioid receptors should be considered in the emergence of establishing evidence of its behavioral activity, our studies pr - e social avoidance behaviors. Our hypothesis was bolstered by sented in this manuscript did not find CERC-501 to be effective earlier studies that reported increased release of endogenous in ameliorating social interaction deficits induced by CSDS. To opioids, and subsequent analgesic effects equivalent to mor - our knowledge, only 3 other studies have previously evaluated phine (75 mg/kg/d), in response to social defeat stress ( Miczek selective KOR antagonists in the CSDS model, and they dif - et al., 1982 ; Vivian and Miczek, 1998; Boyson et al., 2016). This fered from the present study by administering drug treatment effect was blocked by pretreatment with the opioid antagonist during defeat sessions. In the first of these studies, the KOR naltrexone ( Miczek et al., 1982 ). Thus, given that buprenorphine antagonist nor-binaltorphimine given to mice during exposure mediates antidepressant actions via KORs and anxiolytic effects to social defeat for 3 days prevented the development of the with MORs, we hypothesized that both Oprk1 and Oprm1 mRNA stress-induced increases in immobility in the FST, analgesia, expression would be altered in brain regions relevant to social and defeat postures (McLaughlin et al., 2006 ). A second study interaction. Although the mRNA expression analysis is lim - described the effective prevention of social defeat postures dur - ited by the large and heterogeneous nature of gross dissection, ing stress by cotreatment with PF-04455242, a high-affinity KOR which may mask key variations in discrete nuclei of interest, antagonist and moderate MOR antagonist ( Grimwood et al., comparing susceptible mice, that is, those mice that exhibited 2011). Social avoidance behavior and reversal of the effects of significant social avoidance following CSDS with resilient and stress were not directly examined in this study. In a third study, nonstressed control mice allowed for the detection of 2 compel - pretreatment with the KOR antagonist JDTic and genetic disrup - ling findings. tion of KORs on DAT containing neurons prevented increased Oprm1 mRNA expression was decreased in hippocampus and intra-cranial self-stimulation thresholds but did not alter social increased in the frontal cortex following CSDS. Furthermore, a interaction deficits in mice measured following exposure to trend towards a significant decrease in Oprm1 mRNA levels was CSDS (Donahue et al., 2015 ). Taken together, this suggests that in detected in the amygdala. Previous findings from other studies contrast to consistent effects of KOR antagonism on measures using resident intruder and social defeat models in mice and of depression, anxiety, and anhedonia, selective KOR antago - rats have reported alterations in Oprm1 expression, MOR avail - nism did not reverse established patterns of social avoidance, ability, and function following social stress ( Nikulina et al., 1999 , although it may prevent effects of stress if delivered prior to its 2005, 2008; Komatsu et al., 2011 ; Miczek et al., 2011 ; Berube presentation. et al., 2013 ; Johnston et al., 2015 ), especially decreased Oprm1 Ketamine produced robust antidepressant action in the FST mRNA expression in the basolateral amygdala of defeated rats and anxiolytic-like effects in the NIH but was ineffective in the (Berube et al., 2013). Additionally, decreased binding potential CSDS model. Reversal of social interaction deficits after CSDS of MORs in the extended amygdala and increased binding in in mice has been previously reported with ketamine ( Donahue the orbitofrontal cortex has been reported in PTSD patients and et al., 2014 ; Brachman et al., 2016 ), but both studies used higher combat-exposed controls compared with healthy controls with - doses (20–30 mg/kg) than used in this study (10 mg/kg). From our out combat exposure (Liberzon et al., 2007 ). These studies agree data and others, low doses of ketamine (1–10 mg/kg) can alter with our findings, suggesting that the Amy and discreet regions mouse behavior on tests related to antidepressant activity, such of the cortex are stress-sensitive regions for MORs that may be as the FST, NIH test, and reversed the behavioral deficits induced of interest in PTSD. following chronic mild stress ( Autry et al., 2011 ; Browne and Furthermore, expression of Oprk1 mRNA was reduced in the Lucki, 2013). Ketamine produces a variety of pharmacological Amy and increased in the FC after CSDS. Previously, we found effects as doses are gradually increased, ranging from affect - similar changes in Oprk1 mRNA expression following exposure ive change, modeling symptoms of schizophrenia, analgesia to to unpredictable chronic mild stress ( Falcon et al., 2016 ). These ataxia, and anesthesia. It is unclear which effects of ketamine findings highlight the importance of these brain regions in medi- would mediate the effects on social interaction deficits if much ating changes in affective behavior following stress. These data higher doses are required than for antidepressant-like beha - v are also in accord with the clinical literature pertaining to a - ber ioral outcomes. Despite the negative findings presented here, rant prodynorphin signaling and KOR activation in depressed further research into the beneficial effects of ketamine for PTSD patients and the utilization of PET ligands to assay KOR av -ail with other models is warranted, particularly considering the ability as a transdiagnostic maker of dysphoria in patients dia - g emerging clinical evidence that ketamine infusion can rapidly nosed with depression, anhedonia, and PTSD (Hurd et al., 1997 ; reduce symptoms in patients diagnosed with chronic PTSD Hurd, 2002; Anderson et al., 2013 ; Pietrzak et al., 2014 ). Going (Feder et al., 2014 ). forward, studies will interrogate the influence of MOR and KOR Although the mechanisms underlying buprenorphine’s signaling in discreet areas of the Amy and FC in regulating d-ys behavioral effects on social interaction after CSDS are unknown, phoria and negative affect that are relevant to the development evidence suggests that MORs could be involved. Mice with gen - and maintenance of PTSD. etic deletion of MORs do not exhibit social interaction deficits In conclusion, these data highlight the ability of low-dose following exposure to stress ( Komatsu et al., 2011 ). Additionally, buprenorphine in reversing avoidance behavior following social Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/164/4100768 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 172 | International Journal of Neuropsychopharmacology, 2018 defeat and the potential role of both MORs and KORs in re-gu or vulnerability to chronic social defeat stress. Physiology lating behavior following exposure to CSDS. Taken together, Behav 122:237–245. the clinical and preclinical literature have demonstrated many Bodkin JA, Zornberg GL, Lukas SE, Cole JO (1995) Buprenorphine instances of low-dose buprenorphine in reversing negative treatment of refractory depression. J Clin Psychopharm affect or social inhibition Karp ( et al., 2014 ; Falcon et al., 2016 ; 15:49–57. Yovell et al., 2016 ), supporting the need for clinical evaluation Boyson CO, Holly EN, Burke AR, Montagud-Romero S, DeBold of buprenorphine as a therapeutic for PTSD. These preclinical JF, Miczek KA (2016) Maladaptive choices by defeated rats: studies advocate for the continued investigation of compounds link between rapid approach to social threat and escalated capable of modulating both MOR and KOR activity, as these cocaine self-administration. Psychopharmacology 233:3173– compounds may have the most beneficial therapeutic profile for 3186. social deficits, as indicated for PTSD and depression. Brachman RA, McGowan JC, Perusini JN, Lim SC, Pham TH, Faye C, Gardier AM, Mendez-David I, David DJ, Hen R, Denny CA (2016) Ketamine as a prophylactic against stress-induced Funding depressive-like behavior. Biol Psychiatry 79:776–786. This research effort was supported by US Public Health Service Breslau N (2009) The epidemiology of trauma, PTSD, and other posttrauma disorders. Trauma Violence Abuse 10:198–210. (USPHS) grants R01 MH92412, R01 MH105623, and T32 MH14654. Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Acknowledgments Front Pharmacol 4:161. Browne CA, van Nest DS, Lucki I (2015) Antidepressant-like We thank Dr. Jeanine Jochems for her invaluable instruction and effects of buprenorphine in rats are strain dependent. Behav advice in performing the social defeat procedure. Ann Charlot Brain Res 278C:385–392. for assistance in the RT-PCR assays and Dr. Linda Rorick-Kehn Browne CA, Erickson RL, Blendy JA, Lucki I (2017) Genetic vari - for consultation ation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G poly - Statement of Interest morphism. Neuropharmacology 117:401–407. None. 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