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 carbamazep- ine 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 Z01 MH 02528-03 BP). Agents with specific biolog- ical target systems have been used to attempt to modulate carbamazepine's anticonvulsant effects on kindled seizures, in order to elucidate carbam- azepine's mechanisms of action. Finally, studies addressing possible mechanisms of amygdala kindling have been conducted with Drs. Mike Clark, Jeff Rosen, Russel Margolis, De-Maw Chuang, Mark Smith and Trino Baptis- ta. Significant findings to date include demonstration of the following. 1) carbamazepine is an effective anticonvulsant agent during the complet- ed 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 benzod- iazepine receptor (Ro5-4864) and the alpha-2-noradrenergic receptor (yohimbine); 4) amygdala-kindled seizures, electroconvulsive shock seizures, and after discharge activity in the amygdala (without general- ized seizures) can induce CRH-mRNA in the hippocampus, in cells which do not normally express CRH message; 5) kindled seizure development (seizure stage 1-2 or after discharges only) is associated with increased acetyl- choline levels in the amygdala contralateral to the electrode; a less robust increase is observed in fully kindled animals (stage 5 seizures); 6) lesions of the olfactory bulb do not affect the development of amygda- la-kindled seizures or anticonvulsant responsivity to carbamazepine, valproate, or diazepam; 7) time off from seizures, in kindled rats, produces anticonvulsant refractoriness upon subsequent testing; 8) a decrease in seizure threshold (i.e., increased seizure susceptibility) is associated with 5 days of time off from seizures; 9) the proto-oncogene c-fos is induced in a regionally selective manner during kindling devel- opment, which, in the early stages of kindling, is dependent upon the length of the elicited afterdischarge duration; and 10) the mRNA for TRH is increased with amygdala kindling, in roughly the same areas as the c-fos expression.