PHARMACOLOGICAL AND BIOCHEMICAL STUDIES OF AMYGDALA KINDLING

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The objectives of this project are to understand and modulate the course of development of amygdala kindled seizures. The effects of carbamazepine and other anticonvulsants on amygdala kindling have been examined in relation to stage of kindled seizure development (as well as type of kindling stimulus; see above--pharmacological kindling). Agents with specific biological target systems have been used to attempt to modulate carbamazepine's anticonvulsant effects on kindled seizures, in order to elucidate carbamazepine's mechanisms of action. Finally, Studies addressing possible mechanisms of amygdala kindling have been conducted with Drs. Mike Clark, Jeff Rosen, Russel Margolis, and DeMaw Chuang (BPB), and Drs. Mark Smith and Phil Gold (CNE Branch). Significant findings to date include demonstration of the following: 1) carbamazepine is an effective anticonvulsant agent during the completed phase of amygdala kindling, but not during seizure development; 2) valproic acid is an effective anticonvulsant agent against both seizure development and completed seizures; 3) carbamazepine's anticonvulsant effects can be reversed by agents that act at the peripheral-type benzodiazepine receptor (Ro5-4864) and the alpha-2-noradrenergic receptor (yohimbine); 4) amygdala kindled seizures, electroconvulsive shock seizures, and afterdischarge activity in the amygdala (without generalized seizures) can induce CRH-mRNA in the hippocampus, in cells which do not normally express CRH message; 5) lesions of the olfactory bulb do not affect the development of amygdala kindled seizures or anticonvulsant responsivity to carbamazepine, valproate, or diazepam; 6) the absence of seizures in kindled rats produces anticonvulsant refractoriness upon subsequent testing; 7) the proto-oncogene c-fos is induced in a regionally selective manner during kindling development, which, in the early stages of kindling, is dependent upon the length of the elicited afterdischarge duration; and 8) the mRNA for TRH also increased with amygdala kindling, in roughly the same areas as the c-fos expression.