Abstracts

In hippocampal slice preparations, long-term decreases in CA3 burst frequency can be induced by competitive NMDA antagonists due to long-term depression (LTD) at CA3-CA3 synapses. In vitro, this effect is enhanced by application of sequentially lower concentrations of NMDA antagonists. Based on these in vitro results, we hypothesized that administration of successively lower doses of NMDA antagonists would decrease the incidence of electrographic and spontaneous motor seizures in kainate-treated rats. Four 1-year-old rats with kainate-induced epilepsy were implanted with single-channel subdural EEG radiotelemetry units. Baseline EEG and behavioral data was recorded prior to treatment. Each rat was given a series of 3 decreasing doses of SDZ-220-581 (20 mg/kg, 10 mg/kg, and 5 mg/kg, PO) over 3 consecutive days each week for 4 weeks. Continuous EEG recordings and video records were obtained. The computer data were analyzed both by hand and also through routines written in Visual Basic 6.0 to determine seizure frequency before, during and after treatment. The most robust results based on behavioral and EEG analysis were 1) a decrease in seizure duration during SDZ treatment, and 2) a transient increase in total seizure minutes per day, beginning 24 hours after the last dose and peaking 48 hours after the last dose of SDZ. A trend that did not reach significance in these first four animals was a cumulative decline over the 4-week treatment period in seizure duration averaged over the 4 post-SDZ days in each treatment week. The transient increase in seizure activity 48 hours after SDZ likely represents a rebound effect. Given the study design, this rebound obscured most of the anticipated long-term effects of NMDA antagonism. The timing of the rebound suggests that the effective half-life of SDZ was significantly longer than anticipated, so that the concentration-time profile that was effective in vitro was not likely to have been achieved in this in vivo study. To optimize NMDA antagonist dosing in the next series of experiments, in vivo measures of NMDA receptor-dependent LTP and LTD induction will be used to assay the degree of NMDA receptor block. (Supported by NIH, EFA, AES)