Date of Award

8-2021

Degree Name

Doctor of Philosophy

Department

Psychology

First Advisor

Dr. Lisa Baker

Second Advisor

Dr. Alan Poling

Third Advisor

Dr. Ron Van Houten

Fourth Advisor

Dr. Keith Williams

Keywords

Psilocybin, microdose, preclinical, depression, chronic intermittent use, forced swim test

Abstract

Recent studies have demonstrated the clinical efficacy of psychedelic-assisted psychotherapy for treatment-resistant depression and anxiety. Amidst the overall success of recent clinical trials using a single high dose of psilocybin, anecdotal reports indicate anxiolytic and antidepressant effects following a repeated low dose regimen. As therapeutic outcomes are often tightly intertwined with the individual’s subjective experience, animal models are used as objective measures to investigate the underlying mechanisms responsible for the putative antidepressant/anxiolytic effects of psychedelics. Three rodent models predictive of anxiolytic or antidepressant effects were used to evaluate effects of chronic intermittent low dose (CILD) psilocybin treatment; the Light/Dark conflict test (L/D), an open field test (OFT), and the forced swim test (FST). Rats were treated with vehicle or psilocybin (0.025, 0.05, 0.1 mg/kg) every 72 hours over a 48-day period. Tests were conducted 48 hours after the eighth injection (day 24) (L/D, OFT), 48 hours after the 16th injection (day 48) (L/D, OFT, FST), and 12 days after the last injection (day 58) (OFT, FST). Results from the current study indicate that CILD psilocybin does not produce significant differences in exploratory, locomotor, or swimming behavior of rats in the L/D, OFT, or FST paradigms. Rats administered 0.1 mg/kg psilocybin entered the light compartment significantly sooner in the L/D test on day 48 than was observed on day 24. Additionally, rats administered 0.05 or 0.1 mg/kg spent significantly more time in the center of the open field apparatus on day 48 and/or 58 compared to time spent in center on day 24. Measures of stereotypy from the OFT also varied within group, trending in the same direction (reduced stereotypy counts) as saline control animals on day 48 and 58 suggesting that repeated administration of low dose psilocybin does not appear to cause anxiogenic behavior. Overall, the apparent lack of anxiolytic and antidepressant-like effects of CILD psilocybin in the present study suggest that there may be distinct mechanistic and behavioral differences between subthreshold, “microdosing” of psychedelics and hallucinogenic high doses. Future studies with more complex behavioral models, such as operant tasks, or ecologically representative rat populations are warranted to further investigate the behavioral effects of CILD in rodents in order to determine if the cognitive/behavioral effects of “microdosing” reported in humans is exclusively a human phenomenon.

Access Setting

Dissertation-Open Access

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