Abstracts

Rationale: In adult rats, intraperitoneal injection of kainate (KA) results in sustained status epilepticus and persistent behavioral impairments such as hyperactivity, anxiety, and altered response to environment. Intrahippocampal application of KA also results in sustained status epilepticus with rapid bursting in the electroencephalograph (EEG), although long-term behavioral side-effects are unknown. It is also unclear how retigabine, a recently discovered anticonvulsant and potent positive modulator of Kv7 channels, affects seizure-induced behavioral abnormalities. Methods: Status epilepticus was induced with KA (i.p., 15 mg/kg) in adult rats. After a 24 h delay, half of the animals were injected with retigabine (i.p., 2-5 mg/kg) once daily for 14 days. A separate group received a single intrahippocampal injection of KA (1.2 g/ l). All animals underwent three behavioral tests 14 days after status epilepticus and/or 24 h following the last retigabine treatment. These included a capture & handling test, an open field task, and an elevated plus maze task. Intrahippocampal bipolar electrodes or bipolar/cannula assemblies were utilized for EEG recordings and direct delivery of KA.Results: In the capture & handling test, KA peripherally treated rats were frisky, difficult to capture, displayed running, circling, and biting as well as wild attempts to escape for 7-14 days. In contrast, animals post-treated with retigabine showed significant decreases in hyperactive behaviors within 3 days after status epilepticus; they became calm and easier to capture. In the open field test, retigabine treated animals spent significantly more time in the center zone of the apparatus and had greater overall movement (speed and distance traveled) compared to control and KA treated groups. In the elevated plus maze, retigabine animals spent more time in the open arms (proximal and distal) compared to the control group. They also travelled a greater distance overall, suggesting anxiety reduction; however these measurements were not significantly different from peripherally KA treated animals. Interestingly, intrahippocampal KA treated rats were not hyperactive in the capture & handling test nor did they exhibit persistent behavioral side-effects in the open field or elevated plus maze tasks. Conclusions: Anxiolytic-like effects were observed in all three behavioral tasks after peripheral treatment of retigabine. However, KA treated rats also displayed more activity in open arms of the elevated plus maze, suggesting that molecular and subsequent cellular changes induced by the original seizure were partially responsible for the anxiolytic-like effects and that these results are likely independent of the hippocampus.