Date of Award

Winter 12-15-2014

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that serve crucial signaling and neurotrophic functions throughout the central nervous system. Both hyperfunction and hypofunction of NMDARs are associated with neurological and neuropsychiatric conditions. Thus, both positive and negative pharmacological NMDAR modulators are of clinical interest as treatments. Understanding drug mechanisms could lead to more rational drug design. Memantine and ketamine are NMDAR open channel blockers that exhibit similar pharmacodynamics at NMDARs but have different clinical uses. Memantine improves cognitive decline during Alzheimer's disease. Ketamine is an anesthetic and analgesic with psychotomimetic effects, but it is also a rapid acting and long-lived antidepressant. How these mechanistically similar blockers mediate different effects on behavior is unclear, but we hypothesized that unappreciated differences in their pharmacodynamics may contribute. This thesis investigated effects of memantine and ketamine during pathological (excitotoxic) and physiological activity in vitro, where pharmacokinetic effects could largely be ignored. We focused on non-steady state conditions that mimic synaptic transmission. I found that synaptic NMDAR activation is responsible for hypoxic excitotoxic cell death and revealed that memantine, a putative selective extrasynaptic receptor blocker, acquires its selectivity as a result of tonic agonist presentation rather than from affinity for specific populations. Further investigation into the similar synaptic pharmacodynamics of memantine and ketamine revealed a subtle difference in their response to voltage perturbations that was unmasked during physiological activity by increasing the open probability of the channel or by very strong activity. This suggests that regional differences in activity or channel open probability in vivo may control the efficacy of these blockers and partially explain their clinical differences. To further explore properties of ketamine relevant to its antidepressant action, I examined how its pharmacodynamics compares to its major metabolite, norketamine, and to chemical biology analogues of ketamine that show promise in tracking alternative targets for ketamine. In all, these studies reveal mechanistic insights into the pharmacodynamics of two NMDAR channel blockers that may partly explain their clinical effects.

Language

English (en)

Chair and Committee

Steven J Mennerick

Committee Members

James E Huettner, Daniel D Kerschensteiner, Peter D Lukasiewicz, Joseph Henry Steinbach

Comments

Permanent URL: https://doi.org/10.7936/K7WM1BJ6

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