Year: 2024
Type: dissertation
Abstract: Recent clinical trials investigating psychedelics have revealed that they have powerful antidepressive, anxiolytic, and antiaddictive properties, challenging previous notions of psychedelics as “drugs of abuse.” However, these drugs’ mechanisms of action are still poorly understood, limiting their application in broader therapeutic contexts and their utility in investigations of psychiatric conditions. N, N-Dimethyltryptamine (DMT) is a psychedelic that is known to be produced endogenously (internally) in mammals, including humans. It is unclear whether DMT is a trace neurochemical, a neurotransmitter, or something else. DMT has satisfied some (but not all) of the criteria required of classical neurotransmitters such as serotonin, dopamine, and norepinephrine. My work aims to determine whether DMT meets two of these criteria through 1) characterizing the biosynthesis of endogenous DMT in mice, and 2) characterizing the activity of DMT at the vesicular monoamine transporter 2 (VMAT2). Characterizing endogenous DMT biosynthesis in mice may enable the use of viral tools designed to manipulate neural circuits—which are used in mice—to better understand the role of this endogenous hallucinogen in normal functioning of the brain. To search for a mouse biosynthetic pathway for DMT, I expressed potential pathways in cultured mammalian cells and measured DMT in cell lysate and media, which revealed that none of the mouse pathways I tested produced DMT. DMT is thought to be loaded into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2), which accomplishes this for serotonin and dopamine. I expressed a known biosynthetic pathway for DMT in mammalian cells along with VMAT2 and found that vesicle lysate from these cells potentially contained DMT. Ultimately, understanding how DMT is biosynthesized in mice will enable the use of mice as a model for endogenous DMT production and determining if DMT is a substrate of VMAT2 will advance our understanding of endogenous DMT in relation to neurotransmission.
DOI: 10.26153/tsw/64307
Author: Babaian, Emma
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: gold
OpenAlex ID: W7170657208
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