Reversal of Stress-Induced Social Interaction Deficits by Buprenorphine

Abstract

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: CERC-501; PTSD; buprenorphine; chronic social defeat stress; fluoxetine; ketamine; social interaction.

Figure 1.

Buprenorphine reversed social interaction deficits in susceptible mice. Across the 3 testing exposures, non-stressed (NS) mice spent a greater amount of time interacting with the target mouse compared with susceptible CSDS mice (***P<.001, **P<.01). Social interaction scores of susceptible CSDS mice were normalized following 7 days of treatment with buprenorphine compared with mice treated with saline (&P<.05).

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 administration 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).

Figure 3.

Social interaction deficits in susceptible mice were reversed by fluoxetine. Non-stress mice did not exhibit any significant differences in the amount 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 all 3 test days compared with control mice (Figure 3b). Following 7 days but not 24 hours of treatment with fluoxetine (10 mg/kg), social interaction scores of susceptible C57BL/6J mice were restored to a level comparable with control mice (***P<.001 compared with baseline values). No effect was observed with ketamine (10 mg/kg) or CERC-501 (1 mg/kg) treatment.

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.