Pharmacological inhibition of NMDA receptor activity by ketamine is accompanied by pyschotomimetic side-effects; however, the Alzheimers disease therapeutic memantine blocks NMDA receptor activity without debilitating side-effects. This dissertation provides electrophysiological and behavioral characterizations of these two NMDA receptor antagonists in an attempt to understand the unique therapeutic utility of memantine. The following work explores memantine and ketamine inhibition at NMDA receptors, their main site of action, with a focus on the mechanism of inhibition and receptor subtype selectivity in physiologically relevant conditions. This research shows NMDA receptors possess a second binding site at which memantine, but not ketamine, can inhibit activity. The research also shows the dramatic effect physiological concentrations of magnesium has on the ability of these drugs to inhibit NMDA receptor activity. Behavioral and cognitive effects of memantine and ketamine are also assessed and compared directly in rat. The effects of memantine and ketamine in rat were found to be similar at the low doses tested and more divergent as dose increased. Furthermore, memantines effects appeared to be more pronounced and longer-lasting than those of ketamine. These findings demonstrate the importance of considering the physiological environment in which a drug acts, as well as the principles of drug action, when examining the effects of a drug on central nervous system activity.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12112008-131953 |
| Date | 28 January 2009 |
| Creators | Kotermanski, Shawn Edward |
| Contributors | Stefano Vicini, Bita Moghaddam, Stephen D. Meriney, David C. Wood, Jon W. Johnson, Edda Thiels |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12112008-131953/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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