PHARMACOLOGICAL AND BIOCHEMICAL STUDIES OF AMYGDALA KINDLING

项目目标是理解和调整的过程

Project objectives 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. Agents with specific biochemical 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. Studies addressing possible mechanisms of amygdala kindling have been conducted. Most recently, we have developed a novel paradigm 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) carbamazepine is an effective anticonvulsant agent during the completed phase of amygdala kindling, but not during seizure development; 2) 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); 3) amygdala-kindled seizures, electroconvulsive shock seizures, and afterdischarge activity in the amygdala (without generalized seizures) can induce CRH-mRNA in the hippocampus in cells that do not normally express CRH message; 4) time off from seizures, in kindled rats, produces a diminished anticonvulsant response upon subsequent testing and a decrease in seizure threshold; 5) 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; 6) the mRNAs for TRH and a number of other peptides (e.g., NPY, enkephalin, somatostatin) are increased with amygdala kindling. For TRH, this occurs in roughly the same areas as the c-fos expression; 7) under certain circumstances of repeated drug administration and kindling stimulation (i.e., minimally effective doses or lower stimulation intensities), an oscillating anticonvulsant response to carbamazepine and valproate develops. 8) a new paradigm was developed--quenching--whereby low frequency stimulation was demonstrated to produce a long-lasting increase in afterdischarge and seizure thresholds and an inhibition of kindling development. This effect persists for weeks to months (individual variability) after quenching stimulation was discontinued.