The objectives of this project are to understand and modulate the course of development of amygdala kindled seizures. The effects of carbamazepine (CBZ) and other anticonvulsants on amygdala kindling have been examined in relation to stage of kindled seizure development. Agents with specific biochemical target systems have been used to attempt to modulate CBZ's anticonvulsant effects on kindled seizures, in order to elucidate CBZ's mechanisms of action. Studies addressing possible mechanisms of amygdala kindling have been conducted. A novel paradigm has been devised using low frequency stimulation administered in vivo to inhibit kindled seizure development and elevate seizure thresholds. Significant findings to date include demonstration of the following: 1) CBZ is an effective anticonvulsant agent during the completed phase of amygdala kindling, but not during seizure development and its anticonvulsant effects can be reversed by agents that act at the peripheral-type benzodiazepine receptor (Ro5-4864) and the alpha-2-noradrenergic receptor (yohimbine); 2) time off from seizures, in kindled rats, produces a diminished anticonvulsant response and a decrease in seizure threshold (i.e., increased seizure susceptibility); 3) 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; 4) the mRNAs for TRH and a number of other peptides (e.g., CRH, NPY, enkephalin, somatostatin) are increased with amygdala kindling. For TRH, this occurs in roughly the same areas as the c-fos expression; 5) a new paradigm has been developed - quenching - whereby administration of low frequency stimulation to the amygdala produced a long-lasting increase in afterdischarge and seizure thresholds and an inhibition of kindling development and seizure expression in fully kindled animals. This effect persisted for weeks to months after quenching stimulation was discontinued.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Intramural Research (Z01)
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Bladder and Prostatic Cancer Review Committee (BP)
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U.S. National Institute of Mental Health
United States
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