Date of Award
Master of Arts (MA)
College of Humanities and Social Sciences
Thesis Sponsor/Dissertation Chair/Project Chair
Major depressive disorder (MDD) is characterized by emotional distress and cognitive dysfunction that lasts for at least two weeks and significantly impairs one’s ability to function at home and at work. Cognitive deficits in domains such as processing speed, memory retention, and executive function can persist beyond the remission of emotional symptoms, which is why it is imperative to develop antidepressants that address cognitive dysfunction. Healthy cognitive function relies on synaptic plasticity, which strengthens communication between cells and is measured in terms of long-term potentiation (LTP). LTP is triggered when activation of AMPA and NMDA receptors leads to an influx of Ca2+ ions into the cell, and appears to be related to increased AMPA receptor expression. Ketamine, an NMDA receptor antagonist and putative fast-acting antidepressant, results in acute psychotomimetic side effects due to its obstruction of glutamatergic activity at NMDARs. However, 24 hours post-administration, ketamine enhances LTP in the Cornu Ammonis 1 (CA1) region of the hippocampus in rats and enhances AMPA receptor expression. One of ketamine’s metabolites, (2R,6R)-hydroxynorketamine (HNK), manages to enhance AMPA receptor activity in the CA1 of the hippocampus 24 hours post-administration with negligible affinity for the noncompetitive NMDA receptor site, hence avoiding undesirable acute side effects. In rodents, the Novel Object Placement (OP) task is used to assess spatial memory and is dependent on hippocampal function. Therefore, we hypothesized an increase in hippocampal AMPA expression 24 hours post-administration of (2R,6R)-HNK compared to vehicle, which should then result in improved performance in the OP task due to enhanced hippocampal AMPA activity. Our data confirms the increase in hippocampal AMPA expression, but does not reflect this increase in enhanced spatial memory performance in the OP task. Further research is needed on the use of the OP task in conjunction with (2R,6R)-HNK to investigate spatial memory performance, as this may be the first study to do so and thus requires replication. The effects of (2R,6R)-HNK on AMPA expression must also be studied using a chronic stress model with both male and female rats. Differences in glutamatergic neurotransmission that result from chronic stress may help elucidate the mechanisms by which (2R,6R)-HNK exerts its effects.
Khawaja, Anosha, "The Effect of (2R,6R)-hydroxynorketamine (HNK) on 𝛼-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Expression and Novel Object Placement Performance in Long Evans Rats" (2020). Theses, Dissertations and Culminating Projects. 511.
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