Kindling antagonism: an arrest of epileptogenesis?




Kirkby, Robert Duncan

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Concurrent alternating stimulation of two limbic sites culminates in typical kindling of generalized seizures from one site (dominant), whereas the other site (suppressed) supports only nongeneralized seizures for as long as stimulation of the dominant site continues (kindling antagonism). Burchfiel and Applegate (1989; 1990) claimed that antagonism reflects a frank arrest of kindling from the suppressed site at an intermediate stage. They argued, moreover, that the eventual generalization of seizures provoked from the suppressed site after the termination of stimulation of the dominant site reflects a resumption of kindling from its previous state of arrest. Burchfiel and Applegate also claimed that the behaviorally stereotyped arrest of kindling from the suppressed site reveals critical transitions between sequentially expressed mechanisms that govern both antagonism and kindling. They therefore viewed kindling as a stepwise process that is mediated by qualitatively and temporally distinct mechanisms. This position hinges on the assumption that antagonism reflects a true arrest of kindling from the suppressed site rather than a transient inhibition of seizures. I conducted the following experiments to determine whether the assumption is justified, In Experiment 1, I replicated and extended the observations of Burchfiel and Applegate concerning the expression of antagonism during alternating stimulation of limbic as well as nonlimbic sites. The results of Experiment 1 thus indicate that antagonism is indeed a robust phenomenon and therefore worthy of further study. In Experiment 2, the imposition of a prolonged stimulation-free period (30 d) after the termination of stimulation of the dominant site (amygdala) did not significantly reduce the number of stimulations of the suppressed site (septal area) required to elicit a generalized seizure. Also, epileptiform after discharge provoked from the septal area increased during alternating stimulation, and the septal area supported generalized seizures after fewer stimulations in rats previously expressing antagonism as compared to control rats previously kindled from the amygdala. Collectively, these data are consistent with the view of Burchfiel and Applegate that kindling from the suppressed site progresses to an intermediate stage during alternating stimulation and resumes after the termination of stimulation of the dominant site. The results of Experiment 2 also suggest the possibility that the development of seizures from the suppressed site after the termination of stimulation of the dominant site is dictated by the additive expression of: first, the well-documented facilitation of kindling from one site that reliably follows kindling from another (i.e., transfer between the amygdala, which supported generalized seizures, and the septal area); second, (partial) kindling from the septal area, which previously supported nonconvulsive or partial seizures, during the Initial Phase. The results of Experiment 3 revealed that the facilitation of seizure development from the septal area observed in rats previously exposed to alternating stimulation, which perhaps is attributable to partial kindling from the suppressed site, was site specific. Rats subjected to alternating stimulation of the left amygdala and right septal area and control rats previously stimulated only in the left amygdala subsequently demonstrated generalized seizures following similar numbers of stimulations of the previously unstimulated right amygdala. Another plausible view is that antagonism reflects a long-lasting (> 30 d) form of inhibition that is perhaps uniquely invoked by alternating stimulation, While the results of Experiments 1 - 3 do not rule out this possibility, the results of Experiment 4 clearly indicate that the persistence of any such effects of alternating stimulation is not mediated by continuing influences of the dominant site: After the establishment of antagonism, radio-frequency lesions of the dominant site (amygdala) failed to alter the development of seizures provoked by stimulation of the suppressed site (septal area).



Kindling (Neurology)