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.

该项目的目标是理解和调节 点燃和淬火的过程。 点燃涉及发展 反复，间歇性给药后的抽搐 亚行动刺激。 淬火是我们在我们的 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/或放电阈值后。 两种模型 涉及神经系统的长期变化；持久点燃 可能在动物的整个生命中，并持续 中止该程序后至少几个月。 这 已经检查了各种抗惊厥药对点燃的影响 与点燃癫痫发作的阶段有关（例如，发展与发展与 完成与自发的）和点燃刺激的类型（例如， 药理学与电气），表明两者的重要性 与抗惊厥响应有关的参数。 代理 特定的生化目标系统已被用来阐明 抗惊厥药的作用机制和研究也已经 进行以确定杏仁核点燃和淬火的机制。 迄今为止的重大发现包括以下示范。 1） 抗惊厥反应的不同模式基于阶段发生 和点燃刺激的类型；例如，卡马西平是一个有效的 在杏仁核点燃的完整阶段抗惊厥药，但没有 在癫痫发育中，慢性，但不是急性的卡马西平 阻止局部自动智力的开发（但不是表达） 癫痫发作（及其相关的致死性）。 2）胆碱能系统是 参与局部麻醉点燃，对于Procaine和 与利多卡因相比可卡因。 阿托品阻止了由 后者诱发的前和增强性癫痫发作。 Physostigmine 减弱Lidocaine点燃。 3）在杏仁核的老鼠中，休息时间 癫痫发作导致随后的抗惊厥反应减少 测试和癫痫发作阈值降低（即癫痫发作增加 敏感性）表示癫痫发作的功能作用 内源性抗惊厥药适应，似乎是短暂的 促进对外源抗惊厥药的反应。 4）TRH是之一 假设的内源性抗惊厥药适应：以下 Hapocampal内部给药，TRH剂量依赖性地减弱 杏仁核成分的大鼠的屈服和癫痫发作持续时间。 5）mRNA 表达许多直接的早期基因，营养因素和 在点燃过程中以区域选择的方式增加肽 开发以及完成或自发癫痫发作后。 其中一些 区域效应取决于引起的长度 临时;其他人则取决于杏仁核中的位置 发生刺激。 6）已经开发了淬灭 因此低频刺激（除其他参数外 目前正在调查）产生了持久的增加 放电和癫痫发作阈值以及对点燃发展的抑制 和癫痫动物中的癫痫发作。 这些阈值效应 淬灭刺激后持续数周至数月 停产。 7）淬火与增加有关 苯二氮卓受体结合在内嗅和周围皮层中的结合， 但没有产生许多立即的mRNA表达增加 早期基因或TRH。