Fig. 1

Early psilocybin intervention mitigates behavioral alterations induced by chronic stress in a diathesis-stress model of treatment-resistant depression (TRD) using Wistar-Kyoto (WKY) Rats. (A) In the open field test (OFT), rats subjected to social instability stress (SIS) traveled greater distances (cm) than the control (CTL) rats. However, there was no significant increase in the distance traveled between psilocybin-treated rats (SIS-PSI) and sham-treated rats (SIS-Sham). (B) Compared with CTL rats, SIS-Sham rats exhibited a negligible reduction in immobility time (sec), with a minor and nonsignificant difference observed between the SIS-PSI and SIS-Sham subgroups. (C, D) No significant differences were noted in the time (sec) spent in the open or closed arms of the elevated plus maze (EPM) among all groups. (E) The number of entries into the open arms of the EPM did not significantly differ between the CTL and SIS-Sham subgroups; however, the number of entries into the open arms was slightly, though not significantly, greater in the SIS-PSI rats than in the SIS-Sham rats. (F) Compared with CTL rats, SIS-Sham rats engaged in risk assessment behaviors for longer periods (sec). In contrast, compared with those in the SIS-Sham subgroup, the time spent on risk assessment behaviors was lower in the SIS-PSI group. (G) In the forced swim test (FST), the SIS-Sham rats demonstrated greater immobility than the CTL rats, whereas the SIS-PSI rats exhibited less immobility than their SIS-Sham counterparts. (H, I) Notably, compared with those in the SIS-Sham group, the number of climbing and swimming movements (sec) in the SIS-PSI group was significantly greater. (J) Additionally, though modest, the sucrose preference (%) was greater in the SIS-PSI rats relative to the SIS-Sham rats; CTL data were not collected for the SPT. (K) The novel object recognition test revealed a significantly lower recognition index (RI) for the SIS-sham rats than for the CTL rats. In contrast, the SIS-PSI rats achieved a significantly greater RI than did the SIS-Sham rats. The dotted line indicates chance performance (RI = 0.5). For A-G and K, the sample sizes were as follows: CTL, n = 5; SIS-Sham, n = 7; and SIS-PSI, n = 7. The data are presented as the mean ± SEM (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001) and were analyzed by one-way ANOVA followed by Tukey’s post hoc test. For H-J, the sample sizes were as follows: SIS-Sham, n = 7; SIS-PSI, n = 7. The data are expressed as the mean ± SEM (p < 0.05) and were analyzed by two-tailed Mann-Whitney U tests.