PHARMACOLOGICAL, PHYSIOLOGICAL, BIOCHEMICAL AMYGDALA KINDLING/QUENCHING STUDY

这个项目的目标是理解和调整 点火和淬火的过程。引燃涉及到发展 反复、间歇性给药后的抽搐 亚抽搐刺激。淬火是我们开发的一种程序 实验室抑制点燃癫痫的发展和表现 通过提高癫痫发作阈值和/或放电后阈值。两种型号都有 涉及神经系统的长期变化；点燃持续 可能是动物的整个一生，而猝死持续了 在程序终止后至少几个月。这个 不同的抗惊厥药物对点燃的影响已经在 与点燃发作发展阶段的关系(例如，发展与 完成的与自发的)和点燃刺激的类型(例如， 药理学与电学)，表明两者的重要性 与抗惊厥响应性有关的参数。具有以下功能的代理 特定的生化靶标系统已经被用来阐明 抗惊厥药物的作用机制和研究也一直在进行 以确定杏仁核点燃和猝灭的机制。 到目前为止的重大发现包括以下几点的论证。1) 抗惊厥药物反应的不同模式基于不同的阶段 和点燃刺激的类型；例如，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，但不是 在癫痫的发展过程中，慢性但非急性的卡马西平 阻止局部麻醉剂点燃的发展，但不是表达 癫痫(及其相关的致命性)。2)胆碱能系统 参与局部麻醉点燃，与普鲁卡因和普鲁卡因不同 可卡因和利多卡因的对比。阿托品阻断小鼠癫痫发作 前者可增强后者诱发的癫痫发作。毒扁豆碱 减弱利多卡因点燃。3)在杏仁核点燃的大鼠中， 癫痫发作导致随后的抗惊厥反应减弱 测试和癫痫阈值降低(即癫痫发作增加 敏感性)表明癫痫诱发的功能作用 内源性抗惊厥适应，这似乎是短暂的，并 促进对外源性抗惊厥药物的反应。4)TRH是其中之一 假设的内源性抗惊厥药物适应如下： 海马区给药，TRH呈剂量依赖性地减弱 杏仁核点燃大鼠的后放电和癫痫持续时间。5)m RNA 一些即刻早期基因、营养因子和 在点燃过程中，多肽以区域选择性的方式增加 在完全性或自发性癫痫发作后。其中一些 地区性效应取决于所引发的 后放电；其他依赖于杏仁核中 刺激正在发生。淬火已经发展成为一种程序 由此低频刺激(除了其他参数之外 目前正在接受调查)在之后产生了长期的增长 放电和癫痫阈值以及对点燃发展的抑制 以及在完全点燃的动物中的癫痫表现。这些阈值效应 在猝灭刺激后持续数周至数月 停产。7)猝灭与增加 苯二氮卓类受体结合于内嗅觉和嗅周皮质， 但并未产生多个即刻的mRNA表达增加 早期基因或TRH。

The objectives of this project are to understand and modulate the processes of kindling and quenching. Kindling involves the development of convulsions following repeated, intermittent administration of a subconvulsant stimulation. Quenching is a procedure developed in our laboratory to inhibit the development and expression of kindled seizures by increasing the seizure and/or after discharge thresholds. Both models involve long-term changes in the nervous system; with kindling lasting possibly for the entire lifetime of the animal and quenching lasting for at least several months after discontinuation of the procedure. The effects of various anticonvulsants on kindling have been examined in relation to stage of kindled seizure development (e.g., development vs. completed vs. spontaneous) and type of kindling stimulation (e.g., pharmacological vs. electrical), indicating the importance of both parameters in relation to anticonvulsant responsivity. Agents with specific biochemical target systems have been used to elucidate the mechanisms of action of anticonvulsants, and studies have also been conducted to determine mechanisms of amygdala kindling and quenching. Significant findings to date include demonstration of the following. 1) Distinct patterns of anticonvulsant responsivity occur based on the stage and type of kindling stimulation; e.g., carbamazepine is an effective anticonvulsant during the completed phase of amygdala kindling, but not during seizure development, and chronic, but not acute, carbamazepine blocks the development, but not expression, of local-anesthetic-kindled seizures (and their associated lethality). 2) The cholinergic system is involved in local anesthetic kindling and is distinct for procaine and cocaine compared with lidocaine. Atropine blocks seizures induced by the former and potentiates seizures induced by the latter. Physostigmine attenuates lidocaine kindling. 3) In amygdala-kindled rats, time off from seizures leads to a diminished anticonvulsant response upon subsequent testing and a decrease in seizure threshold (i.e., increased seizure susceptibility) indicating a functional role for seizure-induced endogenous anticonvulsant adaptations, which appear to be transient and to facilitate response to exogenous anticonvulsant agents. 4) TRH is one of the hypothesized endogenous anticonvulsant adaptations: following intrahippocampal administration, TRH dose-dependently attenuated the afterdischarge and seizure duration in amygdala-kindled rats. 5) The mRNA expression for a number of immediate early genes, trophic factors, and peptides is increased in a regionally selective manner during kindling development and after completed or spontaneous seizures. Some of these regional effects are dependent upon the length of the elicited afterdischarge; others are dependent on where in the amygdala the stimulation is occurring. 6) Quenching has been developed as a procedure whereby low frequency stimulation (in addition to other parameters currently under investigation) produced a long-lasting increase in after discharge and seizure thresholds and an inhibition of kindling development and seizure expression in fully kindled animals. These threshold effects persisted for weeks to months after quenching stimulation was discontinued. 7) Quenching was associated with increases in benzodiazepine receptor binding in the entorhinal and perirhinal cortices, but did not produce increases in mRNA expression for a number of immediate early genes or TRH.