Abstracts

Rationale: We have previously demonstrated that levetiracetam (LEV) attenuates synaptic transmission in rodent hippocampal slice after a 3 hour drug exposure. However, our earlier experiments did not show the time course of the LEV effect, raising some questions about the true latency. We have now serially assessed synaptic physiology in the same slices in order to more precisly determine when the LEV effect manifests. Methods: Electrophysiology experiments were carried out on 500 μm rat hippocampal slices maintained in a submerged perfusion chamber. The perfusate contained the NMDA antagonist MK-801 to eliminate postsynaptic long term potentiation. A bipolar electrode was used to stimulate the Schaffer collateral fibers and recordings were made from the dendritic layer of CA1. We delivered three trains of stimuli (20 pulses at 40 Hz) every 30 minutes and measured the effect of LEV (100 μM) on the amplitude of each averaged and normalized field EPSP over 3 hours. Results: In the presence of LEV, there was no significant difference in the amplitude of the initial (2-5) field EPSPs over the entire 3 hour perfusion period (n = 6 or 7 slices). However, after 60 min, the later field EPSPs (* beyond the 10th; see Figure) were significantly reduced compared to baseline value. This was not seen in control slices and slices exposed to the inactive LEV enantiomer ucb L060 (100 μM). Under those conditions, the field EPSP actually increased over 0-3 hours. We detected no systematic reduction in the initial EPSP in LEV-exposed slices (n = 6 for each) over 3 hrs Conclusions: These experiments verify our prior observations that LEV does attenuate repetitive synaptic transmission, with a less pronounced effect on initial synaptic responses. The LEV effect requires 60 minutes to appear, possibly explaining the failure of other investigors to observe an in vitro LEV effect on synaptic tranmission. The small potentiation of responses seen over time in control and ucb L060 probably represents a degree of non-NMDA receptor mediated LTP. If true, this suggests that the LEV effect on synaptic transmission might even be larger. The lack of neurological side effects associated with LEV may be partly explained by its relative lack of effect on baseline synaptic transmission. This work was supported by the NIH (R01 NS 042936)