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

Abstract

BackgroundRecent evidence suggests that psychedelics are able to induce rapid and long-lasting antidepressant effects. The generally acknowledged explanation for these traits is the phenomenon of neuroplasticity, although exact underlying molecular mechanisms remain unclear. AimsThis study investigates selected neuroplastic effects of psilocin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) in direct comparison with ketamine, fluoxetine and lithium after acute (1 h) and/or prolonged (24 h) treatment in vitro. MethodsRat primary cortical cultures were treated with 10 {micro}M psilocin, 1 {micro}M lysergic acid diethylamide (LSD), 90 {micro}M N, N-dimethyltryptamine (DMT), 1 {micro}M ketamine, 10 {micro}M 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 immediate early genes (IEGs) encoding activity-regulated cytoskeleton-associated protein (Arc), early growth response 1 (Egr1), and neuronal PAS (Per-ArntSim) domain protein 4 (Npas4) were analysed 1 and 24 h after drug treatments. ResultsPsilocin 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 didnt induce any significant effect. Interestingly, fluoxetine had no effect on synaptic puncta count, but upregulated Egr1 and Npas4. ConclusionsPsilocin demonstrated a significant neuroplastic effect comparable to that of ketamine and lithium, adding another piece of evidence to its profile as a promising therapeutic agent.