EVALUATION OF THE EFFECTS OF PSILOCYBIN ON COGNITION IN AGING MALE AND FEMALE MICE

Major depression is an established risk factor for dementia and may represent a prodromal stage of the disorder. In this context, psychedelic psilocybin has emerged as a promising antidepressant with potential pro-cognitive effects through neuronal plasticity. This study aimed to evaluate the effect of a two-dose psilocybin treatment on cognition in aged mice. Male (n=22) and female (n=21) mice (16-18 months old) received two doses of psilocybin (1 mg/kg i.p.) or saline with a 7-day interval. One week after the last administration, cognitive performance was assessed using the Barnes maze, including an acquisition phase (2 trials per day for 4 days, followed by a test day) and a reversal phase (2 trials per day for 3 days, followed by a test day). Data were analyzed by three-way ANOVA to address the interactions between age, sex and psilocybin treatment. All animals successfully learned the task, as indicated by significant trial effects in both phases (F_{acquisition-time(7,273)}=14.56, p<0.0001; F_{reversal-time(5,195)}=34.41, p<0.0001), but with no overall treatment or sex effects on time spent in the target quadrant during test days. However, females made more errors during the initial acquisition trials (F_sex(1,39)=7.703, p<0.01), but reached the target faster during the first reversal trial (F_sex(1,39)=6.473, p<0.05). Sex-separated two-way ANOVA revealed a significant time x treatment interaction in males during the reversal phase (F_(5,100)=2.678, p<0.05), due to a latency reduction in psilocybin-treated animals in the first trial (-62 ± 23s, p< 0.01). These findings highlight the need to further investigate the pro-cognitive potential of psilocybin considering sex differences.