Date of Award
2024
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Pharmacology
First Advisor
James M. Stafford
Abstract
Mental illnesses including but not limited to anxiety, depression, and Posttraumatic Stress Disorder (PTSD) are among the most significant contributions to disability worldwide and rising suicide rates. Indolamine psychoplastogens such as psilocybin, lysergic acid diethylamide and N,N-Dimethyltryptamine (DMT) have garnered interest in the treatment of mental illnesses as the current standard of care for PTSD, and depressive disorders typically requires several weeks to provide benefit. Specifically, DMT, the hallucinogenic compound in Ayahuasca tea, may provide meaningful effects in treatment resistant populations at psychoactive doses or sub-psychoactive doses in a shorter treatment period. DMT remains less studied in its therapeutic potential and offers a unique opportunity in efficacy given its rapid onset of action, short duration, and high potency. In our studies, we aim to investigate both the acute and lasting effects of intraperitoneal (IP) injected DMT on fear extinction (EXT), alcohol consumption, socialization behavior, and anxiety in C57BL/6J mice. In our first studies, we established DMT dosing based on stereotyped behavior of hallucinogenic effects of DMT with minimal locomotor effects. We found that this dosing immediately prior to fear EXT leads to decreased fear expression with a consistent trend through subsequent tests. This effect suggests an EXT enhancement evidenced by acutely reduced fear expression during EXT. This dose acutely reduced relapse to binge-like drinking in a Drinking in the Dark (DID) paradigm. In our second experiment we sought directly to examine whether chronic, low-dose administration of DMT impacts sociability, fear EXT and anxiety-like behaviors. Here we showed a transient decrease in fear response following reacquisition sessions after treatment. Mice treated with chronic DMT administration also showed a modest increase in preference for socialization as well as increased movement during anxiety trials in elevated plus maze. Lastly, we directly tested the acute effects of DMT at low and moderate doses in a more controlled contextual Fear Conditioning paradigm and observed a similar decrease in fear response during EXT trials immediately following treatment. These mice were also tested for social approach 24 hours after low and moderate doses of DMT dependent on treatment group and displayed and retained preference for socialization compared to controls as well as a modest increase in preference for a novel object relative to controls. The combined results of this study suggest that various doses of DMT under acute and chronic administration paradigms have an impact on learning and behavior which may show promise for therapeutic potential. DMT has consistently shown an effect on behavior throughout all assays, suggesting a possible underlying commonality in chronic and acute administration of DMT on these behaviors resultant of a cognitive effect. Further studies of reward-based learning and exploration behaviors may provide further insight. Our concurrent studies will analyze the effects of chronic DMT administration on biomarkers of synaptogenesis in order to show complementary cellular effects on the potential of DMT for a therapeutic enhancement of novel memory formation.
Language
en
Number of Pages
90 p.
Recommended Citation
George-Hinnant, Caleb Joseph, "Effects Of Acute And Chronic N,n-Dimethyltryptamine On Fear Extinction, Socialization, And Anxiety In Mice" (2024). Graduate College Dissertations and Theses. 1949.
https://scholarworks.uvm.edu/graddis/1949