Novel Treatment Strategies for Major Depressive Disorder: Investigating Ketamine’s Antidepressant Effects and the Role of the c-Jun N-Terminal Kinase Pathway

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Creator: 

Clarke, Melanie J.

Date: 

2019

Abstract: 

Current first-line treatments for depression, namely monoamine-based drugs such as SSRIs, take weeks to show any clinical effects, and they are only effective in 60-70% of patients. There is therefore an urgent need to develop more rapid and efficacious treatments. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist often used as a dissociative anesthetic, has been found to have rapid (within hours) antidepressant effects, even in historically treatment resistant patients. Nevertheless, ketamine has its own limitations, such as unwanted side effects and abuse potential. The overarching goal of this thesis was to gain a better understanding of the antidepressant mechanisms of ketamine. Interestingly, we found that ketamine did not impact the typical stress hormone, corticosterone, nor did it modulate brain-region specific monoamine changes that were induced by acute (restraint) or systemic (lipopolysaccharide; LPS) stressors. However, ketamine did have anti-inflammatory actions, reducing interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and further still, repeated ketamine treatment promoted adult neurogenesis within the hippocampus. Notably, repeated ketamine also had an antidepressant-like behavioral effect that was still detectable 8 days after the final ketamine injection. In terms of potential mechanistic factors, ketamine increased active levels of the signaling factor c-Jun N-terminal kinase (JNK) within the cortex, and inhibition of JNK itself increased corticosterone levels. Intriguingly, JNK inhibition also modulated some stress-induced behavioral and monoaminergic changes, implying a diverse role for the protein. Overall, the data support a role for ketamine in neuroplasticity and immune function, and set the stage for future investigations into the pathways (i.e. JNK) associated with its antidepressant effects.

Subject: 

Neuroscience

Language: 

English

Publisher: 

Carleton University

Contributor: 

co-author: 
Shawn Hayley
co-author: 
Shawn Hayley
co-author: 
Hymie Anisman
co-author: 
Darcy Litteljohn
co-author: 
Jessica Bobyn
co-author: 
Natalie Prowse
co-author: 
Rowan Pentz
co-author: 
Sara Razmjou
co-author: 
Zach Dwyer
Publisher: 
Journal Copyright Documentation

Thesis Degree Name: 

Doctor of Philosophy: 
Ph.D.

Thesis Degree Level: 

Doctoral

Thesis Degree Discipline: 

Neuroscience

Parent Collection: 

Theses and Dissertations

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