MECHANISM OF CANNABINOID ANTI-CONVULSANT EFFECTS

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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.