MECHANISM OF CANNABINOID ANTI-CONVULSANT EFFECTS

我们实验室已经证明，在匹罗卡品的获得性癫痫模型中，癫痫的诱导 在大麻素受体的表达中产生基本上永久性的神经元可塑性变化 (CB1)是大脑中含量最丰富的G蛋白偶联受体之一。我们还展示了这部小说 癫痫动物CB1表达的神经元可塑性变化导致两者显著降低 发作频率和持续时间。尽管大麻类化合物已被证明具有抗惊厥作用和 一直被认为是治疗癫痫的可能替代疗法，但目前还没有实验室 关于重复使用和退出的研究！大麻类药物在治疗癫痫动物中的作用。我们的试点研究与 统计验证表明，重复使用大麻类药物治疗癫痫发作可能会加剧癫痫发作。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 剂量大麻素给药，既最初阻止耐受性发展到的癫痫发作，又 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，甚至 癫痫动物的癫痫持续状态；目的2：验证重复常数增加的假说 大麻药剂量给药导致耐受性的发展和停药！引起变化 CB1受体在癫痫动物大脑中的表达；目标3：检验以下假设 重复、恒定和递增剂量的大麻素给药导致 容忍和撤退！引起由CB1刺激的G蛋白评估的CB1受体功能的变化 癫痫动物大脑中的激活；目标4：检验重复常数和 加大剂量大麻类药物的给药，导致耐受性的发展和停药！成因 通过CB1受体结合特性的改变来评估CB1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，并 撤退！模拟娱乐使用和滥用大麻类药物的发作频率和持续时间 以及CB1受体在已建立的匹罗卡品癫痫大鼠模型中的表达和功能。这 研究将确定是否重复服用大麻素并停药！在模拟癫痫的动物中 人类滥用大麻素会导致癫痫发作障碍的永久性恶化，甚至会导致SE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.