Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning
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Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of “fear conditioning” may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.
KeywordsNeurogenesis Psilocybin Serotonin Hippocampus Learning Memory Trace conditioning
This work was supported by the Helen Ellis Research Endowment (J.S.R.). Thanks to David Nichols Ph.D. for donating the selective 5-HT2A agonist 25I-NBMeO and Dr. Francisco Moreno from University of Arizona and Rick Doblin Ph.D. of the Multidisciplinary Association for Psychedelic Studies (MAPS) for donating the PSOP.
- Esclassan F, Coutureau E, Di SG, Marchand AR (2009) Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning. Hippocampus 19:33–44Google Scholar
- Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry 68:71–78Google Scholar
- Klempin F, Babu H, De Pietri TD, Alarcon E, Fabel K, Kempermann G (2010) Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci 3:1–11. Art No 14Google Scholar
- Moreno FA, Wiegand CB, Taitano EK, Delgado PL (2006) Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry 67:1735–1740Google Scholar
- Young SN (2013) Single treatments that have lasting effects: some thoughts on the antidepressant effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin. J Psychiatry Neurosci 38:78–83Google Scholar