Effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression – comparison with ketamine, fluoxetine and lithium

Background: Recent evidence suggests that psychedelics can induce rapid and long-lasting antidepressant effects. The generally acknowledged explanation for these traits is the phenomenon of neuroplasticity, although the exact underlying molecular mechanisms remain unclear. Aims: This study investigates the effects of psilocin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) on synaptogenesis and immediate early genes (IEGs) expression in direct comparison with ketamine, fluoxetine and lithium after acute (1 h) and/or prolonged (24 h) treatment in vitro. Methods: Rat primary cortical cultures were treated with 10 µM psilocin, 1 µM LSD, 90 µM DMT, 1 µM ketamine, 10 µM fluoxetine and 5 mM lithium. Analysis of synaptic puncta was performed; puncta of presynaptic marker synapsin I/II, postsynaptic density protein 95 (PSD-95) and their co-localization (established synapse) were assessed 24 h after drug treatment. Next, expressions of IEGs encoding activity-regulated cytoskeleton-associated protein ( Arc ), early growth response 1 ( Egr1 ), and neuronal PAS (Per-Arnt-Sim) domain protein 4 ( Npas4 ) were analysed 1 and 24 h after drug treatments. Results: Psilocin increased synaptic puncta count and induced Arc expression. The effect to promote synaptogenesis was comparable to ketamine and lithium; ketamine additionally increased PSD-95 puncta count. LSD and DMT did not induce any significant effects. Interestingly, fluoxetine had no effect on synaptic puncta count, but upregulated Egr1 and Npas4 . Conclusions: Psilocin demonstrated synaptogenic effects comparable to those of ketamine and lithium, and acutely upregulated IEG Arc expression, adding another piece of evidence to its profile as a promising therapeutic agent.