The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice

Abstract

Social avoidance and social phobia are core symptoms of various psychopathologies but their underlying etiology remains poorly understood. Therefore, this study aims to reveal pro-social effects of the neuropeptide oxytocin (OT), under both basal and stress-induced social avoidance conditions in rodents using a social preference paradigm. We initially show that intracerebroventricular (i.c.v.) application of an OT receptor antagonist (OTR-A) in naïve male rats (0.75 μg/5 μl), or mice (20 μg/2 μl), reduced social exploration of a novel con-specific indicative of attenuated social preference. Previous exposure of male rats to a single social defeat resulted in loss of their social preference and social avoidance, which could be restored by i.c.v. infusion of synthetic OT (0.1 μg/5 μl) 20 min before the social preference test. Although the amygdala has been implicated in both social and OT-mediated actions, bilateral OTR-A (0.1 μg/1 μl) or OT (0.01 μg/1 μl) administration into various subnuclei of the amygdala did not affect basal or stress-induced social preference behavior, respectively. Finally, we demonstrate the social specificity of these OT-mediated effects by showing that neither an arginine vasopressin V1a receptor antagonist (0.75 μg/5 μl, i.c.v.) nor the anxiogenic drug pentylenetetrazol (15 mg/kg, i.p.) altered social preference, with OTR-A not affecting non-social anxiety on the elevated plus-maze. Overall, the data indicate that the basal activity of the endogenous brain OT system is sufficient to promote natural occurring social preference in rodents while synthetic OT shows potential to reverse stress-induced social avoidance and might thus be of use for treating social phobia and social dysfunction in humans.

Figure 1

Effects of i.c.v. administration of an oxytocin receptor antagonist (OTR-A; rats: 0.75 μg/5 μl; mice 20 μg/2 μl) or vasopressin receptor antagonist (V1aR-A, rats: 0.75 μg/5 μl) on social preference in a novel arena (rats and mice; see schematic drawing) or in the home cage (rats). Social preference is reflected by the higher percentage of investigation time directed toward the social (black columns) vs the object (grey columns) stimulus during two sequential exposures. Numbers in parentheses reflect group size. Data are means+SEM, ^#p<0.05 vs object stimulus, ^*p<0.05 vs vehicle, (^*) p=0.055 vs vehicle; two-way ANOVA for repeated measures followed by Bonferroni post hoc test.

Figure 2

Effects of infusion of an oxytocin receptor antagonist (OTR-A, 0.1 μg/1 μl and 1.0 μg/1 μl) bilaterally into the central, medial, or basolateral amygdala on social preference behavior of male rats. Social preference is reflected by the higher percentage of investigation time directed toward the social (black columns) vs the object (grey columns) stimulus during two sequential exposures. Numbers in parentheses reflect group size. Data are means+SEM, ^#p<0.05 vs object stimulus, two-way ANOVA for repeated measures followed by Bonferroni post hoc test.

Figure 3

Social preference behavior of socially defeated and control rats. (a) Control and defeated rats were exposed to an unknown male as social stimulus during the social preference test. (b) Socially defeated rats were exposed to their individual defeater rat as social stimulus during the social preference test. Social preference is reflected by a higher percentage of investigation time directed toward the social (black columns) vs the object (grey columns) stimulus during two sequential exposures. Numbers in parentheses reflect group size. Data are means+SEM, ^*p<0.05 vs non-defeated control, ^#p<0.05 vs object stimulus; two-way ANOVA for repeated measures followed by Bonferroni post hoc test.

Figure 4

Social preference behavior of socially defeated and control rats after either vehicle (Veh) or oxytocin (OT) were applied i.c.v. (0.1 μg/5 μl, a) or bilaterally into the central (ceA) or medial (meA) amygdala (b) (0.01 μg/1 μl) 20 min prior to the social preference test. Social preference is reflected by the higher percentage of investigation time directed toward the social (black columns) vs the object (grey columns) stimulus during two sequential exposures. Numbers in parentheses reflect group size. Data are means+SEM, ^#p<0.05 vs object stimulus; three-way or two-way ANOVA for repeated measures followed by Bonferroni post hoc test.

Figure 5

(a) Effects of i.c.v. infusion of an oxytocin receptor antagonist (OTR-A, 0.75 μg/5 μl) on non-social anxiety in the black–white box in rats and on the elevated plus-maze in mice, respectively. Non-social anxiety is reflected by the percentage of time spent in the white box of the black–white box and the percentage of time spent on the open arms in the elevated plus-maze. (b) Effects of PTZ (15 mg/kg, i.p.) on non-social anxiety and locomotion of male rats on the plus-maze. Data are means+SEM, ^*p<0.05 vs vehicle, Students's t-test. (c) Effects of PTZ on social preference in rats reflected by the higher percentage of investigation time directed toward the social vs the object stimulus. Data are means+SEM, ^#p<0.05 vs object stimulus, two-way ANOVA for repeated measures followed by Bonferroni post hoc test.