Modulation of Pilocarpine-Induced Seizures by Cannabinoid Receptor 1

Administration of the muscarinic agonist pilocarpine is commonly used to induce seizures in rodents for the study of epilepsy. Activation of muscarinic receptors has been previously shown to increase the production of endocannabinoids in the brain. Endocannabinoids act at the cannabinoid CB₁ receptors to reduce neurotransmitter release and the severity of seizures in several models of epilepsy. In this study, we determined the effect of CB₁ receptor activity on the induction in mice of seizures by pilocarpine. We found that decreased activation of the CB₁ receptor, either through genetic deletion of the receptor or treatment with a CB₁ antagonist, increased pilocarpine seizure severity without modifying seizure-induced cell proliferation and cell death. These results indicate that endocannabinoids act at the CB₁ receptor to modulate the severity of pilocarpine-induced seizures. Administration of a CB₁ agonist produced characteristic CB₁-dependent behavioral responses, but did not affect pilocarpine seizure severity. A possible explanation for the lack of effect of CB₁ agonist administration on pilocarpine seizures, despite the effects of CB₁ antagonist administration and CB₁ gene deletion, is that muscarinic receptor-stimulated endocannabinoid production is acting maximally at CB₁ receptors to modulate sensitivity to pilocarpine seizures.