MECHANISM OF CANNABINOID ANTI-CONVULSANT EFFECTS

我们实验室证明毛果芸香碱获得性癫痫模型可诱发癫痫 大麻素受体的表达产生本质上永久性的神经元可塑性变化 (CB1)，大脑中最丰富的 G 蛋白偶联受体之一。我们还表明这部小说 癫痫动物中 CB1 表达的神经元可塑性变化导致 癫痫发作频率和持续时间。尽管大麻素已被证明具有抗惊厥作用 已被提倡作为癫痫病的可能替代疗法，但没有实验室 关于重复使用和退出的研究！大麻素治疗癫痫动物。我们的试点研究 统计验证表明，用大麻素重复治疗癫痫发作可能会使癫痫发作恶化。我们 将进行以下具体目标： 目标1：检验重复常数和递增的假设 大麻素的给药剂量既能最初阻止癫痫发作，又能产生耐受性 随后的大麻素戒断将导致癫痫发作频率和持续时间增加，甚至 癫痫动物的癫痫持续状态（SE）；目标 2：检验重复不断增加的假设 剂量大麻素给药导致耐受性和戒断的发展！引起变化 癫痫动物大脑中 CB1 受体的表达；目标 3：检验假设 重复恒定和增加剂量的大麻素施用导致发展 宽容与退缩！通过 CB1 刺激的 G 蛋白评估，导致 CB1 受体功能发生变化 癫痫动物大脑的激活；目标 4：检验重复常数和 增加大麻素的给药剂量，导致耐受性和戒断的发展！原因 通过 CB1 受体结合特征的改变来评估 CB1 受体功能的变化。这个 研究建议评估重复使用大麻素的后果和基本机制 撤退！模拟娱乐性使用和滥用大麻素对癫痫发作频率和持续时间的影响 以及对已建立的毛果芸香碱大鼠癫痫模型中 CB1 受体表达和功能的影响。这个 研究将确定是否重复使用大麻素并退出！在癫痫动物中模拟 人类滥用大麻素可导致癫痫症永久性恶化，甚至因 SE 导致死亡。

Our laboratory has demonstrated that the induction of epilepsy in the pilocarpine model of acquired epilepsy produces an essentially permanent neuronal plasticity change in the expression of the cannabinoid receptor (CB1), one of the most abundant G-Protein coupled receptors in brain. We have also shown that this novel neuronal plasticity change in CB1 expression in the epileptic animal causes a significant decrease in both seizure frequency and duration. Although cannabinoids have been shown to have anticonvulsant effects and have been advocated as possible alternative treatments for seizure disorders, there are no laboratory studies on repetitive use and withdraw! of cannabinoids in treating epileptic animals. Our pilot studies with statistical validation suggest that repetitive treatment of seizures with cannabinoids can worsen seizures. We will conduct the following specific aims: AIM 1:To test the hypothesis that repetitive constant and increasing dose cannabinoid administration that both initially block seizures to which tolerance develops and subsequent cannabinoid withdrawal will lead to an increase in seizure frequency and duration and even to status epilepticus (SE) in epileptic animals; AIM 2: To test the hypothesis that repetitive constant increasing dose cannabinoid administration that leads to the development of tolerance and withdraw! causes changes in the expression of the CB1 receptor in the brains of epileptic animals; Aim 3: To test the hypothesis that repetitive constant and increasing dose cannabinoid administration that leads to the development of tolerance and withdraw! causes changes in the CB1 receptor function as assessed by CB1 stimulated Gprotein activation in the brains of epileptic animals; Aim 4: To test the hypothesis that repetitive constant and increasing dose cannabinoid administration that leads to the development of tolerance and withdraw! causes changes in the CB1 receptor function as assessed by alteration of CB1 receptor binding characteristics. This study proposes to evaluate the consequences and basic mechanisms of repetitive cannabinoid use and withdraw! that simulate the recreational use and abuse of cannabinoids on seizure frequency and duration and on CB1 receptor expression and function in the well established pilocarpine rat model of epilepsy. This study will determine if repetitive cannabinoid administration and withdraw! in epileptic animals that simulates cannabinoid abuse in man can cause permanent worsening of seizure disorders and even death by SE.