Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Psychology
First Advisor
Joseph H. Porter,
Second Advisor
Katherine L. Nicholson
Abstract
Depression stands as one of the most pervasive mental health challenges worldwide, including the United States. Conventional antidepressants typically display a delayed onset of therapeutic action (4-8 weeks) and lack efficacy in a substantial portion of patients (over 40% of depressed patients are treatment-resistant). The dissociative anesthetic ketamine, which is a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, has emerged as a promising novel treatment due to its rapid and prolonged antidepressant effects, and it is especially beneficial for treatment-resistant depression. Nevertheless, the precise neurochemical mechanisms underlying ketamine’s antidepressant properties remain elusive, hampering the development of safer and more efficacious treatments. The present study examined the potential involvement of the opioid system in ketamine’s antidepressant and cognitive effects through experimentation on three strains of rats. The non- selective opioid antagonist naltrexone was tested alone and in combination with ketamine in several preclinical assays. Additionally, the investigation explored possible pharmacokinetic interactions between ketamine and naltrexone. Finally, this study assessed the validity of the rodent model of differential reinforcement of low rate (DRL) 72s as a screening test for antidepressant efficacy, drawing comparisons between the therapeutic time courses of traditional monoamine antidepressants (desipramine and bupropion) and ketamine. The synthesis of findings from the four studies included in this dissertation revealed two main discoveries. Firstly, naltrexone pretreatment inhibits the metabolic process of ketamine, indicating a potential mechanism by which naltrexone may affect ketamine's effects. Additionally, behavioral assessments suggested that this pharmacokinetic interaction could enhance ketamine's acute cognitive effects while delaying or reducing its antidepressant-like effects. These findings introduce a new hypothesis addressing the debate among researchers regarding how naltrexone influences ketamine's antidepressant-like effects. The second noteworthy finding underscores the limitations of the DRL 72s task in accurately reflecting the clinically relevant therapeutic time courses of both novel antidepressant ketamine and well-established monoamine antidepressants like the tricyclic antidepressant desipramine and the norepinephrine-dopamine reuptake inhibitor bupropion. This discovery casts doubt on the predictive validity of DRL 72s task as a reliable tool for screening potential antidepressants. Findings suggest that the traditional tests used for antidepressant screening may not adequately capture the nuanced effects of existing antidepressants, highlighting the need for more comprehensive and nuanced screening approaches in antidepressant research.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-30-2024
Included in
Animal Studies Commons, Behavior and Behavior Mechanisms Commons, Biological Psychology Commons, Experimental Analysis of Behavior Commons, Mental Disorders Commons, Pharmacology Commons