PHARMACOLOGICAL AND BIOCHEMICAL STUDIES OF AMYGDALA KINDLING

项目目标是理解和调整 杏仁核点燃癫痫的发展。卡马西平的疗效观察 和其他对杏仁核点燃的抗惊厥药物已经在 与点燃发作发展阶段的关系。具有特定身份的代理 生化靶标系统已经被用来试图调节 卡马西平对点燃癫痫的抗惊厥作用 阐明卡马西平的作用机制。研究寻址 杏仁核点燃的可能机制已经被进行了研究。多数 最近，我们开发了一种使用低频的新范式 体内刺激抑制点燃癫痫的发展 并提高癫痫发作阈值。到目前为止的重要发现包括 论证：1)卡马西平是一种有效的 杏仁核点燃完成阶段的抗惊厥药物，但 2)卡马西平的抗惊厥作用 可被作用于外周型苯二氮卓类的药物逆转 受体(Ro5-4864)和α-2-去甲肾上腺素能受体(育亨宾)； 3)杏仁核点燃的癫痫、电惊厥性休克癫痫，以及 杏仁核后放电活动(无全身性惊厥) 可以在海马区诱导CRH-mRNA在不正常的细胞中 表达CRH信息；4)癫痫发作后的休息时间，在点燃的大鼠中产生 在随后的测试中，抗惊厥反应减弱， 降低惊厥阈值；5)原癌基因c-fos被诱导 在火种开发过程中有区域选择性的方式，在 点燃的早期阶段，取决于被引燃的长度 后放电持续时间；6)TRH和其他一些的mRNAs 多肽(如NPY、脑啡肽、生长抑素)随着 杏仁核点燃。对于TRH，这发生在大致相同的区域 C-fos的表达；7)在某些情况下重复用药 给药和点燃刺激(即最低有效剂量 或较低的刺激强度)，一种振荡的抗惊厥反应 对卡马西平和丙戊酸盐的影响。8)一个新的范式是 开发的--猝灭--由此演示了低频刺激 使后放电和癫痫发作持续增加 阈值和对点燃发展的抑制。这一效果 猝灭后持续数周至数月(个别情况不同) 刺激停止了。

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.