Defense Date


Document Type


Degree Name

Master of Science


Physiology and Biophysics

First Advisor

Dr. Javier González-Maeso

Second Advisor

Dr. Vijay Lyall

Third Advisor

Dr. Jennifer Wolstenholme


In recent years, there has been a growing interest in psychedelic compounds stemming from their promising use as therapeutic agents and research tools that can be used to treat and study several neuropsychiatric disorders. Psychedelics have proven useful in a broad range of these diseases - they serve as models for psychosis in schizophrenia but have also had promising results in treating major depressive disorder, anxiety, and other common disorders. Decreased stigmatization surrounding psychedelics has further increased their use in research and clinical settings. In light of these trends and the promising nature of their use, a thorough understanding of the mechanisms underlying their action is necessary. The Serotonin 2A Receptor, or 5-HT2AR, has been shown to play a major role in neuropsychiatric disorders and also serves as the primary receptor mediating psychedelic action. In rodent models, administration of psychedelics such as the phenethylamine-derived compound 2,5-dimethoxy-4-iodoamphetamine (DOI) produces a behavior known as the head twitch response. This characteristic head movement occurs as the specific result of 5-HT2AR activation by psychedelic substances and in tandem with characteristic psychedelic genotypic expression pathways, and can, therefore, be used to quantify 5-HT2AR activation. Repeated administration of psychedelics has also been shown to lead to tolerance, producing diminished therapeutic effects for otherwise promising treatments. In animal models, tolerance can be demonstrated using the HTR model, quantified through progressive decreases in the number of head twitch behaviors elicited upon psychedelic administration. While several theories have attempted to explain the mechanisms behind tolerance, they remain unknown and are worthy of further study.

My project aimed to examine signaling pathways underlying psychedelic action, the head twitch response, and tolerance in order to more fully understand the mechanisms behind these processes. My results indicate that the Mitogen-Activated Protein Kinase, ERK, plays a role in mediating the head twitch response acutely, highlighting this signaling pathway as a mediator of this behavioral response. However, signaling blockade at the level of ERK failed to prevent tolerance development. Interestingly, signaling blockade at the level of Protein Kinase C (PKC) failed to diminish head twitch acutely and also failed to prevent tolerance. Finally, pre-treatment with the 5-HT2AR specific antagonist M100,907 attenuated head twitch acutely but similarly failed to prevent tolerance. Collectively, these results point towards the MAP Kinase pathway as important in mediating psychedelic induced head twitch behavior, but further study is needed to investigate the source of tolerance.


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