Defense Date
2025
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmacology & Toxicology
First Advisor
Dr. Sammanda Ramamoorthy
Second Advisor
Dr. Hamid Akbarali
Third Advisor
Dr. Ian Scott Ramsey
Abstract
Major depressive disorder (MDD) affects over 350 million individuals worldwide and is characterized by profound dysregulation of serotonin (5-HT) and dopamine (DA) systems that govern mood, reward processing, and motivation. The serotonin transporter (SERT) and dopamine transporter (DAT), both dynamically regulated through phosphorylation, serve as critical determinants of synaptic monoamine signaling. Despite decades of therapeutic development, current antidepressants require 4-6 weeks to achieve efficacy, and approximately one-third to half of patients develop treatment-resistant depression. The emergence of rapid-acting antidepressants like ketamine represents a paradigmatic shift, demonstrating symptom relief within hours; however, ketamine's therapeutic potential remains constrained by abuse liability, dissociative effects, and requirement for clinical supervision. Growing evidence suggests scopolamine, a non-selective muscarinic antagonist with demonstrated 5-HT₃ receptor binding, exhibits rapid antidepressant properties within days, potentially through modulation of mesolimbic dopaminergic circuits via M5 receptors and serotonergic circuits via hippocampal-prefrontal-raphe connectivity. Despite scopolamine's established clinical efficacy, no studies have systematically investigated whether its therapeutic effects involve direct modulation of SERT and DAT function in mood-regulatory brain regions, or whether such neurochemical adaptations correlate with behaviorally relevant antidepressant-like effects, a critical gap for developing safer, more targeted rapid-acting therapeutics for treatment-resistant depression.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-1-2025