MECHANISM OF CANNABINOID ANTI-CONVULSANT EFFECTS

我们的实验室已经证明，在获得性癫痫的毛果芸香碱模型中， 在大麻素受体的表达中产生基本上永久的神经元可塑性变化 (CB1)是脑内最丰富的G蛋白偶联受体之一。我们还发现这部小说 癫痫动物中CB 1表达的神经元可塑性变化导致两者的显著降低， 发作频率和持续时间。虽然大麻素已被证明具有抗惊厥作用， 已经被提倡作为癫痫发作障碍的可能替代治疗，没有实验室 研究重复使用和撤回！大麻素在治疗癫痫动物中的应用我们的试点研究， 统计学验证表明，用大麻素重复治疗癫痫发作可使癫痫发作恶化。我们 目的1：检验重复常数和递增的假设， 剂量的大麻素给药，其最初阻断产生耐受的癫痫发作， 随后的大麻素戒断将导致癫痫发作频率和持续时间的增加， 目的2：验证癫痫动物的癫痫持续状态（SE）; 剂量大麻素管理，导致发展的耐受性和撤回！导致变化 在癫痫动物脑中CB 1受体表达中的作用;目的3：检验以下假设： 重复恒定和增加剂量的大麻素施用，导致 宽容与退缩！引起CB 1受体功能的变化，如CB 1刺激的G蛋白所评估的 目的4：验证重复常数和重复频率对癫痫动物脑中的激活的影响。 增加剂量大麻素管理，导致耐受性和撤回的发展！原因 通过改变CB 1受体结合特征评估CB 1受体功能的变化。这 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 和CB 1受体的表达和功能在良好建立的匹罗卡品癫痫大鼠模型。这 研究将确定是否重复大麻素管理和撤回！在癫痫动物中， 在人中滥用大麻素可导致癫痫病的永久性恶化，甚至因SE而死亡。

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.