Photochemical Sciences Ph.D. Dissertations

Phenylethylamine Derivatives: Pharmacological and Toxicological Studies

Date of Award

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Photochemical Sciences

First Advisor

Jon Sprague (Advisor)

Second Advisor

Raymond Larsen (Committee Member)

Third Advisor

Travis Worst (Committee Member)

Fourth Advisor

Craig Zirbel (Other)

Abstract

The purpose of this dissertation is to discuss the theory, methodology and assessment of the pharmacological and toxicological effects of phenylethylamines in two targeted areas: First, viability of utilizing a retrodialysis in vivo experimental model to assess the differences in synaptic dopamine (DA) concentrations under direct perfusion of two structurally and yet pharmacodynamically different synthetic cathinones (“bath salts”). Second, the relationship between the mechanisms underlying phenylethylamine-induced hyperthermia (PIH) and gut microbiome composition and diversity, a research area which remains poorly investigated in the current literature. For the first part of our research, we suggest the utilization of retrodialysis technique to locally deliver the drugs under investigation to the targeted brain area and assess the resulting changes in DA concentrations using High Performance Liquid Chromatography Coupled with Electrochemical Detection (HPLC-EC). We report that retrodialysis was successfully incorporated to deliver synthetic cathinones to the caudate putamen while utilizing HPLC-EC detection to assess extracellular DA changes within the targeted area. In the second part of our research, we suggest a new approach in exploring the relationship between PIH mechanisms and gut microbiome structure and richness by employing bidirectional fecal microbial transplant (FMT) via oral gavage as a method of transferring the hyperthermic phenotypic response upon methamphetamine (METH) treatment between male and female rat models. Through this modality, we can observe the changes in gut microbiome populations at each stage of treatment and how these changes affect PIH. We observe that although bidirectional FMT model employed repopulated the gut of the respective animals, gut microbiome does not seem to play a role in the sex-based differences in PIH between male and female rats. For the third part of the presented research, we explored the role of the gut-adrenal axis in 3,4-methylenedioxymethamphetamine (MDMA) treatment in SHAM and adrenalectomized (ADX) rat model. Additionally, we sought to observe the changes in core body temperature and gut microbiome structure and richness after exogenous administration of corticosterone (CORT) or norepinephrine (NE) to ADX animals. We observe distinct differences in the hyperthermic response and gut microbiome diversity before and after treatment in all animal groups assessed.

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