PHARMACOLOGICAL, PHYSIOLOGICAL, BIOCHEMICAL AMYGDALA KINDLING/QUENCHING STUDY

杏仁核药理学、生理学、生物化学点燃/淬灭研究

• 批准号: 6162961
• 负责人: R M POST
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162961
• 关键词: amygdala; anticonvulsants; benzodiazepine receptor; brain electrical activity; carbamazepine; cocaine; drug interactions; electrostimulus; generalized seizures; hippocampus; kindling; laboratory rat; lidocaine; neuropharmacology; physostigmine; procaine; receptor binding; thyrotropin releasing hormone

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.

本项目的目标是了解和调节 点燃和熄灭的过程。 点燃涉及到 反复间歇给药后惊厥 亚惊厥刺激 淬火是一种在我们的 实验室抑制点燃癫痫发作的发展和表达 通过增加癫痫发作和/或放电后阈值。 两种模型 涉及神经系统的长期变化;点燃持续 可能持续动物的整个寿命， 至少在手术停止后几个月。 的 各种抗惊厥药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 完全对自发）和点燃刺激的类型（例如， 药理学与电学），表明两者的重要性 与抗惊厥药反应有关的参数。 剂与 特定的生物化学靶系统已被用于阐明 抗惊厥药的作用机制，研究也已 以确定杏仁核点燃和淬灭的机制。 迄今为止的重要调查结果包括以下方面的证明。 第一章 不同的抗惊厥药反应模式发生的阶段的基础上 和点燃刺激的类型;例如，卡马西平是一种有效 杏仁核点燃完成阶段的抗惊厥药，但不 在癫痫发作过程中，慢性而非急性卡马西平 阻断局部麻醉点燃的 癫痫发作（及其相关的致命性）。 2)胆碱能系统是 参与局部麻醉点燃，与普鲁卡因不同， 可卡因与利多卡因相比。 阿托品可阻断 前者和后者诱发的癫痫发作增强。 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， 测试和癫痫发作阈值的降低（即，癫痫发作增加 易感性），表明对糖尿病诱导的 内源性抗惊厥适应，这似乎是短暂的， 促进对外源性抗惊厥剂的反应。 4)TRH是一种 假设的内源性抗惊厥适应： 海马内给药，TRH剂量依赖性地减弱 杏仁核点燃大鼠的后放电和癫痫发作持续时间。 5)的mRNA 许多立即早期基因、营养因子和 在点燃过程中， 发展和完成或自发性癫痫发作后。 其中一些 区域影响取决于引发的时间长度 后放电;其他依赖于杏仁核的位置， 刺激正在发生。 6)淬火已经发展成为一种程序， 由此低频刺激（除了其它参数之外 目前正在调查）产生了长期的增加后， 放电和癫痫发作阈值以及抑制点燃发展 和癫痫发作的表达。 这些门槛效应 持续数周至数月后淬火刺激， 停止了。 7)淬火与增加 内嗅和嗅周皮质中的苯二氮受体结合， 但在一些即时的实验中， 早期基因或TRH。