Norepinephrine and E139 interactions on epileptiform activity in the rat hippocampus in vitro

Abstract

Objectives: We tested if E139, an anticonvulsant enaminone, interacts with norepinephrine (NE) to suppress population responses and chemically induced in vitro seizures in the rat hippocampus. Materials and Methods: Evoked field population spikes (PS) were recorded in the hippocampal CA1 area, and in vitro seizures were generated chemically using the zero Mg2+ model. Results: Low concentrations of E139 (≤10 μM) reversibly inhibited PS amplitude while high concentrations (≥100 μM) enhanced them. For example, E139 (10 μM) depressed the PS amplitude by -23.9 ± 2.3%, while 1 mM caused an enhancement. NE also depressed the PS by -34.5 ± 6.0% and prevented E139 from subsequently depressing the PS amplitude. UK 14304, a selective α2-adrenoceptor agonist, also depressed the PS amplitude by -32.6 ± 9.4% and occluded E139 suppression. NE suppression of PS was blocked by phentolamine and yohimbine which also blocked the effect of E139. Prazosin, a selective α1-adrenoceptor antagonist, did not block NE (-24.8 ± 6.9%) or E139 (-29.7 ± 6.1%) effects. Zero Mg2+ buffer transformed a single PS to multiple spikes (MS; 3-8 spikes) and also induced spontaneous bursts (SB; 5-20/min). NE suppressed the number of MS from 5.6 ± 0.3 to 3.8 ± 0.2. At its peak effect, E139 was able to further suppress the number of MS to 3.0 ± 0.3. Yohimbine did not change the number of MS but blocked the NE- and E139-induced suppression of MS. SB frequency was suppressed by NE (-60.8 ± 11.7%) which occluded E139 effects. Finally, SB were reversibly abolished by yohimbine (-94.5 ± 11.7%). Conclusion: E139 suppressed population responses and in vitro epileptiform activity by both adrenergic and non-adrenergic mechanisms. Copyright © 2008 S. Karger AG.