Abstracts

We previously reported that topiramate inhibits both the AMPA and kainate components of the excitatory synaptic response elicited by stimulation of the amygdalar capsule, but is substantially more potent on the component of the response mediated by GluR5 kainate receptors than AMPA receptors. We proposed that selective blockade of kainate receptors is key factor in the therapeutic activity of topiramate. Recognizing that topiramate contains an aminosulfonyl functional group as does cyclothiazide and other cyclothiazide-like modulators of AMPA receptor desensitization, we sought to determine whether topiramate alters the time course of AMPA receptor mediated synaptic responses.
Whole-cell patch recordings were made from visually identified BLA principal neurons in 450 [micro]m-thick coronal slices from the rat brain. Bipolar tungsten electrode placed on the amygdalar capsule, synaptic responses were evoked with 100 [micro]s monophasic stimuli. AMPA receptors were isolated by perfusing a cocktail of antagonist including 100 [micro]M D-AP5, 10 nM LY 293558, 10 [micro]M bicuculline methiodide, and 10[micro]M SCH 50911 to block NMDA, kainate, GABA[sub]A[/sub] and GABA[sub]B[/sub] receptors, respectively.
The mean peak AMPA receptor current amplitude was 1594 [plusmn] 398 pA, the mean 10-90% rise time was 7.7 [plusmn] 4.8 ms and the mean 90-10% decay time was 23.2 [plusmn] 4.6 ms (7 slices); the mean decay time constant value ([tau][sub]c[/sub]) from single exponential fits was 11.6 [plusmn] 1.4 ms. Topiramate (0.1[ndash]10 mM) caused modest reduction in the peak amplitude of the AMPA receptor mediated synaptic response associated with a significant slowing of the decay time constant by 189 [plusmn] 150% for 1 [micro]M topiramate and 156 [plusmn] 151% for 10 [micro]M topiramate (p[lt]0.004), without a significant change in the rise time. Topiramate did not significantly affect the 10-90% rise time or the 90-10% decay time of GluR5 kainate receptor synaptic currents, which were, respectively, 6.1 [plusmn] 1.1 ms and 39.2 [plusmn] 6.7 ms under control conditions.
Topiramate slowed the time course of AMPA but not kainate receptor mediated synaptic currents, an action that could be due to effects on AMPA receptor desensitization similar to that of cyclothiazide. Cyclothiazide-like desensitization modulators not only slow AMPA receptor desensitization, but also increase the peak amplitude of AMPA receptor currents. It is interesting to speculate that, while topiramate may block (reduce the amplitude) of both AMPA and kainate currents, its relatively weaker activity on AMPA currents could be due to an effect on AMPA receptor desensitization that would functionally oppose (partially reverse) the block. The overall weak activity of topiramate on AMPA receptors likely accounts for its lack of dramatic neurobehavioral side effects in comparison with more potent CNS AMPA receptor antagonists. The extent to which prolongation of AMPA receptor current decay contributes to the various clinical actions of topiramate remains to be determined.
[Supported by: NINDS]