Abstracts

RATIONALE: Although the mechanism of action of the anticonvulsant topiramate is poorly understood, there is evidence that the drug may affect glutamatergic excitatory neurotransmission though an interaction with AMPA/kainate receptors. We have demonstrated that GluR5 kainate receptors mediate a portion of the synaptic excitation of basolateral amygdala (BLA) principal neurons evoked by external capsule (EC) stimulation. In this study, we used selective antagonists to isolate the AMPA and GluR5 kainate receptor components of the EC-evoked excitatory synaptic current (EPSC) and compared the effects of topiramate on these two distinct EPSC components. We also examined the possibility that topiramate acts indirectly via effects on protein phosphorylation.
METHODS: Whole-cell patch recordings were carried out from visually identified BLA principal neurons in 450- [mu]m coronal slices of rat amygdala. Synaptic currents were evoked with 100-[mu]s monophasic stimuli applied via a tungsten bipolar electrode placed on the EC. Mixed AMPA and GluR5 kainate receptor responses were isolated by perfusion with 100 [mu]M D-AP5, 10 [mu]M bicuculline methiodide and 10 [mu]M SCH 50911 to block the NMDA, GABAA and GABAB receptors, respectively. AMPA receptor currents were further isolated by addition of 10 nM LY 293558, which at these low concentrations selectively blocks GluR5 kainate receptors. Conversely, the GluR5 kainate receptor component was isolated with 50 [mu]M GYKI 52466, a selective AMPA receptor antagonist.
RESULTS: Topiramate perfusion caused a concentration-dependent reduction in the amplitude of the GluR5 response, with nearly complete block at 10 nM. The blocking action of topiramate was uncharacteristically slow, suggesting that the drug may not directly interact with GluR5 kainate receptors. In contrast, the AMPA receptor-mediated component of the response was much less sensitive to topiramate with only minimal block at concentration as high as 10 [mu]M. The effect of topiramate was mimicked by the protein kinase A (PKA) inhibitor H-89 (1 [mu]M), consistent with the possibility that topiramate may selectively block GluR5 kainate receptors by modulating PKA-dependent phosphorylation of GluR5 kainate receptors or related proteins
CONCLUSIONS: The ability of topiramate to selectively block kainate receptors and not AMPA receptors could contribute to its unique anticonvulsant properties and its relatively low side effects compared with other types of glutamate receptor antagonists. Our preliminary studies support the view that topiramate acts via a nonconventional modulatory mechanism.
[Supported by: NINDS-NIH]