Abstracts

Disruptions in GABAergic neurotransmission have been implicated in numerous CNS disorders, including epilepsy, depression, bipolar disorder, and neuropathic pain. Selective inhibition of neuronal and glial GABA transporter subtypes may offer unique therapeutic options for regaining balance between inhibitory and excitatory systems. Even so, the differential effect of GAT-1 and nonGAT-1 transport inhibitors on spontaneous electrographic activity remains unclear. Previous work has shown that spontaneous electrographic bursting recorded in the medial entorhinal cortex (mEC) of slices made from kainic acid (KA)-treated rats were resistant to therapeutic concentrations of traditional anticonvulsants (carbamazepine and phenytoin), but were successfully blocked by the novel anticonvulsant retigabine (Smith-Yockman, 2003). In the present study, this [italic]in vitro[/italic] model is being used to evaluate the ability of GABA transport inhibitors to modulate inhibitory tone via the mGAT-1 (tiagabine) or the mGAT-1/BGT-1 (EF-1502) transporter. Both spontanteous bursts (SB) and evoked field potentials were recorded in combined mEC-HC horizontal brain slices (400[mu]m; 31[plusmn]1[deg]C) made one week after KA-induced seizure activity [italic]in vivo[/italic]. The effects of EF-1502 and tiagabine were tested at concentrations ranging from 3-30 [mu]M for their ability to modulate SB frequency, fEPSP area, and fEPSP duration. Effects were considered significant if p[lt]0.05 versus baseline recordings using Student[apos]s t-test analysis. The investigational drug EF-1502 displayed a dose-dependent reduction in SB frequency without significant effect on the either duration or area of the evoked response from Layer II of the mEC. At 30[mu]M, the average SB rate was reduced to 54.3% of the burst rate recorded prior to bath application of the drug. Tiagabine (3-30[mu]M) was unable to significantly inhibit the frequency of SB activity recorded in the mEC, however, it did reduce the both duration (55.7% of baseline) and the area (35.5% of baseline) of evoked responses at doses as low as 3[mu]M. The ability of EF-1502, but not tiagabine, to inhibit spontaneous electrographic bursting in the mEC demonstrates that this [italic]in vitro[/italic] model is sensitive enough to differentiate between novel anticonvulsants with similar mechanisms of action and also suggests a therapeutic potential for non-GAT1 transport inhibitors. (Supported by NINDS contract # NO1-NS-4-2359 and by NINDS grant NS-4-9624 (HSW).)