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As one of the leading causes of disease burden and disability in the world, Major Depressive Disorder (MDD) is a persistent and ever expanding financial and public health concern. MDD is quite prevalent in children and adolescents with life-long negative consequences. Although there are treatments available for MDD, they lack in effectiveness, and have a potential for enduing negative side effects. These conventional treatments are even less effective in pediatric MDD as more than 50% of these patients are deemed treatment-resistant. Ketamine (KET), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has recently shown great promise as a rapid-acting and long-lasting treatment for MDD, especially for treatment-resistant MDD. Unfortunately, the efficacy, functionality, and biochemical consequences of KET exposure during periods prior to adulthood are not known. Therefore, the following sets of experiments were designed to examine the antidepressant efficacy of KET during adolescence as well as the potential neurobiological mechanisms involved. To do this, behavioral reactivity to stress- and anxiety-eliciting situations and responsiveness to KET treatment were characterized in adolescent male rats and mice in chapters two and three. Data presented in these chapters demonstrated that KET is an effective antidepressant in adolescent rodents; however, the neurobiological underpinning(s) mediating these effects required examination. Recent evidence has shown that KET reverses the deficits associated with stress within major mesocorticolimbic regions such as the prefrontal cortex (PFC), Nucleus Accumbens (NAc), and hippocampus. However little is known about KET’s effect in the ventral tegmental area (VTA), which provides the majority of dopaminergic input to these regions. Therefore, the experiments conducted in chapter four were designed to examine the neurobiological underpinnings of KET’s antidepressant effects in adolescent male mice. More specifically, the biochemical and electrophysiological effects produced by KET treatment during adolescence were characterized within the VTA and its major projection regions, the NAc and PFC, respectively. Combined, the findings within this dissertation indicate that KET treatment produces antidepressant-like effects in adolescence, and that these effects are mediated, at least in part, by changes in intracellular signaling and neuronal activity within VTA dopamine neurons and its connection to the NAc. Lastly, in chapter five, the potential clinical implications as well as future directions of this work are discussed.
A Dissertation submitted to the Department of Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Carlos A. Bolaños-Guzmán, Professor Directing Dissertation; Branko Stefanovic, University Representative; Frank Johnson, Committee Member; Sanjay Kumar, Committee Member; Walter Boot, Committee Member.
Florida State University
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