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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.

2019-12-06 neuroscience
10.1101/866814 bioRxiv
Show 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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