d-Lysergic acid diethylamide has major potential as a cognitive enhancer

Cini, F. A.; Ornelas, I.; Marcos, E.; Goto-Silva, L.; Nascimento, J.; Ruschi, S.; Salerno, J.; Karmirian, K.; Costa, M.; Sequerra, E.; de Araujo, D. B.; Tofoli, L. F.; Renno-Costa, C.; Martins-de-Souza, D.; Feilding, A.; Rehen, S.; Ribeiro, S.

doi:10.1101/866814

bioRxiv · 10.1101/866814

d-Lysergic acid diethylamide has major potential as a cognitive enhancer

Cini, F. A.·Ornelas, I.·Marcos, E.·Goto-Silva, L.·Nascimento, J.·Ruschi, S.·Salerno, J.·Karmirian, K.·Costa, M.·Sequerra, E.·de Araujo, D. B.·Tofoli, L. F.·Renno-Costa, C.·Martins-de-Souza, D.·Feilding, A.·Rehen, S.·Ribeiro, S.

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Abstract

Psychedelic agonists of serotonin receptors induce neural plasticity and synaptogenesis, but their potential to enhance learning remains uncharted. Here we show that a single dose of d-LSD, a potent serotonergic agonist, increased novel object preference in young and adult rats several days after treatment. d-LSD alone did not increase preference in old animals, but could rescue it to young levels when followed by a 6-day exposure to enriched environment (EE). Mass spectrometry-based proteomics in human brain organoids treated with d-LSD showed upregulation of proteins from the presynaptic active zone. A computational model of synaptic connectivity in the hippocampus and prefrontal cortex suggests that d-LSD enhances novelty preference by combining local synaptic changes in mnemonic and executive regions, with alterations of long-range synapses. Better pattern separation within EE explained its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.

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Cini, F. A., Ornelas, I., Marcos, E., Goto-Silva, L., Nascimento, J., Ruschi, S., Salerno, J., Karmirian, K., Costa, M., Sequerra, E., de Araujo, D. B., Tofoli, L. F., Renno-Costa, C., Martins-de-Souza, D., Feilding, A., Rehen, S., Ribeiro, S.. 2019-12-06. d-Lysergic acid diethylamide has major potential as a cognitive enhancer. https://doi.org/10.1101/866814

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