a, Schematic timeline of experimental design. b, Mice showed no preference for either empty cage during habituation for the social interaction assay (Sham-Oxy-Veh n = 8, Sham-Oxy-RBC1HI n = 10; SNI-Oxy-Veh n = 8, SNI-Oxy-RBC1HI n = 7; same for all phases). c, Sociability test: data are shown as the percentage of time spent by subject mice in the social target-containing field and empty cage-containing field. All groups of mice showed preference for the social target, except for the SNI-Oxy group (SNI two-way ANOVA interaction F1,26 = 3.209, P = 0.0849; Sidak’s multiple comparisons SNI-Oxy-RBC1HI social target versus no target t = 3.88, d.f. = 26, P = 0.0013). d, Social novelty recognition: data are shown as the percentage of time spent by subject mice in the stranger 1-containing field and stranger 2-containing field (SNI two-way ANOVA interaction F1,26 = 9.833, P = 0.0042; Sidak’s multiple comparisons SNI-Oxy-RBC1HI familiar versus stranger, t = 4.331, d.f. = 26, P = 0.0004). e, Treatment with RBC1HI decreased anxiety-like behaviors in the marble-burying assay 2 weeks after oxycodone withdrawal in both SNI and sham groups of male and Sham-Oxy female mice (Sham-Sal-Veh n = 7, Sham-Sal-RBC1HI n = 9; Sham-Oxy-Veh n = 8, Sham-Oxy-RBC1HI n = 10; SNI-Sal-Veh n = 7, SNI-Sal-RBC1HI n = 9; SNI-Oxy-Veh n = 8, SNI-Oxy-RBC1HI n = 7; SNI two-way ANOVA interaction F1,27 = 21.1, P < 0.0001; Sidak’s multiple comparisons SNI-Oxy-RBC1HI versus SNI-Oxy-Veh t = 8.324, d.f. = 27, P < 0.0001; Sham two-way ANOVA interaction F1,30 = 1.303, P = 0.2627; Sidak’s multiple comparisons Sham-Oxy-RBC1HI versus Sham-Oxy-Veh t = 3.119, d.f. = 30, P = 0.008). f, RBC1HI treatment reduced immobility time in SNI-Oxy mice (Sham-Sal-Veh n = 7, Sham-Sal-RBC1HI n = 7; Sham-Oxy-Veh n = 7, Sham-Oxy-RBC1HI n = 10; SNI-Sal-Veh n = 7, SNI-Sal-RBC1HI n = 9; SNI-Oxy-Veh n = 7, SNI-Oxy-RBC1HI n = 6; two-way ANOVA drug treatment F1,52 = 4.787, P = 0.0332; Sidak’s multiple comparisons SNI-Oxy-Veh versus SNI-Oxy-RBC1HI t = 2.627, d.f. = 52, P = 0.0444). Data indicate the mean ± s.e.m. Significance was calculated by means of two-way ANOVA with Bonferroni’s post hoc test; *P < 0.05, ***P < 0.001 and ****P < 0.0001.