Effects of Serotonergic Psychedelics on Synaptic Function and Neuroplasticity

INTRODUCTION: Sertonergic psychedelics LSD, psilocin and DMT, have been shown to hold a great potential for treatment of various neuropsychiatric conditions, such as major depressive disorder, addiction, and end-of-life anxiety. Effects of these substances on neuronal activity and plasticity have been demonstrated, however, better understanding of their mechanism of action is crucial for development of novel therapies. OBJECTIVES: This study aimed to determine the effects of serotonergic psychedelics LSD, psilocin and DMT on the neurotransmitter release and neuronal network activity, and furthermore to explore possible molecular players involved in this modulation. METHODS: We used genetically encoded sensors of synaptic vesicle fusion, synaptopHluorin, of glutamate release, iGluSnFR, and of presynaptic calcium levels, synGCaMP6, expressed in primary rat cortical cultures, to monitor the effects of psychedelics on key presynaptic mechanisms. Pharmacological approach using agonists and antagonists of 5-HT receptors was utilised to study the involvement of specific receptor types. Furthermore, we used immunofluorescence staining and western blotting to assess levels and phosphorylation states of several key regulators of presynaptic properties and plasticity. Finally, neurones grown on microelectrode arrays were utilised to analyze acute effects of psychedelics on neuronal network activity. RESULTS: Psychedelics decreased the proportion of synaptic vesicles undergoing fusion in response to mild or strong electrical stimulation upon 3-30 min treatment, while these effects were no longer present following 24 h treatment. Furthermore, DMT and psilocin increased evoked response at glutamatergic synapses following single stimulation, while at the same time psilocin decreased the paired-pulse facilitation. LSD and psilocin reduced evoked presynaptic calcium transients. On the level of network activity, LSD and DMT strongly inhibited spontaneous neuronal firing, while evoked responses remained unaltered. CONCLUSIONS: While we observed substance-specific effects revealed by various approaches, all tested psychedelics converged on inhibition of neurotransmission. The modulation of neurotransmission described here expands the understanding of the acute action of psychedelics, however, further research is required to elucidate the relationship between the synaptic effects of psychedelics, alterations in network activity, and the therapeutic effects of psychedelics.