Fig. 4: Effects of 5-HT2AR and 5-HT1AR antagonism on psilocybin-induced improvements in reversal learning.

Reversal learning following 5-HT2AR antagonism via pre-treatment with MDL100907 (A) was completely impaired in saline treated animals (0/9 [0%] reached reversal day 1 criterion) whereas psilocybin treatment prevented this impairment (5/9 [55.6%] reached criterion). Psilocybin treatment following MDL-mediated 5-HT2AR antagonism resulted in significantly greater session accuracy (B, t(16) = 3.034, p = 0.0079), pellets earned (C, t(16) = 2.255, p = 0.385), and target pokes made (D, t(16) = 2.191, p = 0.0436) compared to saline treatment, with no differences for non-target pokes (E, t(16) = 0.7609, p = 0.4578), first poke latency (time from device access to first poke; F, t(16) = 1.034, p = 0.3163), target poke latency (G, t(11) = 0.5098, p = 0.6202), relative first pellet latency (time from first poke to earning first pellet;(H), t(6) = 1.295, p = 0.2428), or session duration (time from first to final poke; (I), t(16) = 1.133, p = 0.2741). The opposite performance pattern was observed following 5-HT1AR antagonism via WAY100635 pre-treatment (J), with 7/13 (53.8%) saline treated rats reaching criterion compared with only 2/13 (15.4%) psilocybin treated rats. Although not significant, psilocybin treatment produced a trend toward lower session accuracy (K, t(24) = 2.011, p = 0.0556), fewer pellets earned (L, t(24) = 1.806, p = 0.0834), and target pokes made (M, t(24) = 1.771, p = 0.0893), whilst there was no difference between groups for non-target pokes (N, t(24) = 1.317, p = 0.2001), first poke (O, t(24) = 0.7925, p = 0.4538), target poke (P, t(19) = 0.1996, p = 0.8440), or relative first pellet (Q, t(14) = 0.3062, p = 0.7639) latency, or session duration (R, t(24) = 0.1337, p = 0.8948). Bar graphs show mean ± SEM with individual data points. *p < 0.05, **p < 0.01. SAL saline, PSI psilocybin. For full statistical analysis details see Fig. 4 Statistics Table.