Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology and Biophysics

First Advisor

Javier González-Maeso

Abstract

Psychedelics are a class of hallucinogenic substances that exert their effects through serotonin (5-HT) receptor agonism, particularly at the 5-HT2 receptor, which is further characterized into the 2A, 2B, and 2C subtypes. While some research studies indicate that psychedelics mediate their effects via 5-HT2A receptor agonism, others show that it is not necessary to induce these effects. Recently, there has been a growing interest in psychedelic-assisted therapy as a promising alternative for treatment of anxiety and depression, two of the most common psychiatric disorders worldwide associated with significant morbidity. Although antidepressants and pharmacological interventions for anxiety have revolutionized management, they often have mixed efficacy and fail to provide satisfactory emotional relief. Clinical studies show that psychedelics like psilocybin and LSD produce antidepressant and anxiolytic effects, but there is still an active debate on whether or not these effects are mediated via action at the 5-HT2A receptor.

In this study, my first aim was to examine psilocybin’s effects on the following behavioral assays in male WT C57BL/6 mice: head-twitch response (HTR), a 5-HT2A-specific rodent model of hallucinogenic action; locomotor activity, a model of anxiety; novel object recognition (NOR), to assess recognition memory; light-dark box preference, an additional model of anxiety; and forced swim test (FST), a model of depression-like behavior. HTR assessed the acute effects of psilocybin, while the remaining assays measured psilocybin’s post-acute effects (i.e. 24 hrs following administration). Second, I aimed to determine whether or not psilocybin’s post-acute antidepressant-like effects are mediated by the 5-HT2A receptor by conducting FST assays using the 5-HT2A-specific antagonist volinanserin (M100,907). Acutely, psilocybin evoked a greater HTR relative to the vehicle group, but post-acutely it did not produce a significant difference in locomotion, NOR, or light-dark exploratory behavior. However, mice given psilocybin in the first FST had both lower immobility and higher climbing times relative to controls. In the second FST, mice administered M100,907 shortly before injection with psilocybin exhibited no significant difference in immobility and climbing times compared to controls. Interestingly, in the third FST, mice given M100,907 alone had a significantly lower climbing time, while immobility and swimming times between the vehicle and experimental groups were nonsignificant. The results of this study suggest that the 5-HT2A receptor may indeed play a central role in mediating psychedelics’ post-acute effects, and that antagonizing it impairs these effects. These findings highlight the need for additional studies that examine the post-acute effects of a variety of psychedelics and further investigate the level of involvement of the 5-HT2A receptor using genetically modified animal models.

Rights

© Nikita Thakur

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

6-16-2022

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