MECHANISM OF BLOCK AND BEHAVIORAL EFFECTS OF THE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS MEMANTINE AND KETAMINE

摘要

Pharmacological inhibition of NMDA receptor activity by ketamine is accompanied by pyschotomimetic side-effects; however, the Alzheimer's 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, memantine's 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.