PHARMACOLOGICAL, PHYSIOLOGICAL,& BIOCHEMICAL AMYGDALA KINDLING & QUENCHIN

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The objectives of this project are to understand and modulate the processes of kindling and quenching. Kindling involves the development of convulsions following repeated, intermittent administration of a subconvulsant stimulation. Quenching is a procedure developed in our laboratory to inhibit the development and expression of kindled seizures by increasing the seizure and/or afterdischarge thresholds. Both models involve long-term changes in the nervous system; with kindling lasting possibly for the entire lifetime of the animal and quenching lasting for weeks to months after discontinuation of the procedure. The effects of various anticonvulsants on kindling have been examined in relation to stage of kindled seizure development (e.g., development vs. completed vs. spontaneous) and type of kindling stimulation (e.g., pharmacological vs. electrical), indicating the importance of both parameters in relation to anticonvulsant responsivity. Agents with specific biochemical target systems have been used to elucidate the mechanisms of action of anticonvulsants, and studies have also been conducted to determine mechanisms of amygdala kindling and quenching. Significant findings to date include demonstration of the following. 1) Distinct patterns of anticonvulsant responsivity occur based on the stage and type of kindling stimulation; e.g., carbamazepine is an effective anticonvulsant during the completed phase of amygdala kindling, but not during seizure development, and chronic, but not acute, carbamazepine blocks the development, but not expression, of local-anesthetic-kindled seizures (and their associated lethality). 2) The cholinergic system is involved in local anesthetic kindling and is distinct for procaine and cocaine compared with lidocaine. Atropine blocks seizures induced by procaine and cocaine and potentiates seizures induced by lidocaine. Physostigmine attenuates lidocaine kindling. 3) In amygdala-kindled rats, time off from seizures leads to a diminished anticon-vulsant response upon subsequent testing and a decrease in seizure threshold (i.e., increased seizure susceptibility), indicating a functional role for seizure-induced endogenous anticon-vulsant adaptations, which appear to be transient and to facilitate response to exogenous anticonvulsant agents. 4) TRH is one of the hypothesized endogenous anticonvulsant adaptations: following intrahippocampal administration, TRH dose-dependently attenuated the afterdischarge and seizure duration in amygdala-kindled rats. 5) The mRNA expression for a number of immediate early genes, trophic factors, and peptides is increased in a regionally selective manner during kindling development and after completed or spontaneous seizures. Some of these regional effects are dependent upon the length of the elicited afterdischarge; others are dependent on where in the amygdala the stimulation is occurring. 6) Quenching paradigms have been developed using very low levels (LL) of direct current (DC) with or without concurrent low frequency stimulation which produce a long-lasting increase in afterdischarge and seizure threshold, and an inhibition of kindling development and seizure expression in fully kindled animals. These threshold effects persisted for weeks to months after quenching stimulation was discontinued. 7) Quenching was associated with increases in benzodiazepine receptor binding in the entorhinal and perirhinal cortices, but did not produce increases in mRNA expression for a number of immediate early genes and TRH. 8) DC quenching is associated with local increases in the mRNA for glial acid fibulary protein and a strip of silver deposition, raising the question of whether a microscopic lesion is being produced by the LL-DC and of its ultimate clinical relevance. 9) DC has also been utilized in the amygdala slice preparation wherein it induces homosynaptic but not heterosynaptic inhibition that can be overridden by increasing intensity of stimulation.