PHARMACOLOGICAL AND BIOCHEMICAL STUDIES OF AMYGDALA KINDLING

杏仁核点燃的药理学和生物化学研究

• 批准号: 5203746
• 负责人: S R WEISS
• 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/5203746
• 关键词: alpha adrenergic receptor; amygdala; anticonvulsants; benzodiazepine receptor; carbamazepine; corticotropin releasing factor; drug interactions; electrostimulus; gene induction /repression; hippocampus; kindling; laboratory rat; molecular psychobiology; neuropharmacology; protooncogene; thyrotropin releasing hormone; valproate; yohimbine

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.

项目目标是了解和调整 杏仁核点燃癫痫发作 卡马西平的作用 和其他抗惊厥药对杏仁核点燃的影响已经在 与点燃癫痫发作发展阶段有关。 具有特定 生物化学靶系统已被用于尝试调节 卡马西平对点燃癫痫发作的抗惊厥作用， 阐明卡马西平的作用机制。 研究讨论 杏仁核点燃的可能机制已经进行。最 最近，我们开发了一种新的范例， 体内给予刺激以抑制点燃癫痫发作发展 并提高癫痫发作阈值 迄今为止的重要调查结果包括 证明：1）卡马西平是有效的 杏仁核点燃完成阶段的抗惊厥药，但 而不是在癫痫发作过程中; 2）卡马西平的抗惊厥作用 可通过作用于外周型苯二氮卓类药物逆转 受体（Ro 5 -4864）和α-2-去甲肾上腺素能受体（育亨宾）; 3)杏仁核点燃癫痫发作，电休克癫痫发作， 杏仁核后放电活动（无全身性癫痫发作） 可以在海马体中诱导CRH-mRNA，而在正常情况下， 表达CRH信息; 4）癫痫发作的时间，在点燃大鼠中，产生 在随后的测试中抗惊厥反应减弱， 癫痫发作阈值降低; 5）原癌基因c-fos被诱导 在点燃发展过程中的区域选择性方式， 点燃的早期阶段，取决于引发的时间的长短。 后放电持续时间; 6）TRH和一些其他的mRNA 肽（例如，神经肽Y，脑啡肽，生长抑素）增加， 杏仁核点燃 对于TRH，这发生在大致相同的区域， c-fos表达; 7）在一定的重复用药情况下 给药和点燃刺激（即，最低有效剂量 或较低的刺激强度），振荡抗惊厥反应 卡马西平和丙戊酸盐的反应 8)一个新的范例是 开发-淬火-其中低频刺激被证明是 产生持续增加的后放电和癫痫发作 阈值和抑制点燃发展。 这种效果 淬灭后持续数周至数月（个体差异） 停止刺激。