Pro-epileptic effects of the cannabinoid receptor antagonist SR141716 in a model of audiogenic epilepsy

• Published in: Epilepsy research 2011-10, Vol.96 (3), p.250-256
• Main Authors: Vinogradova, Lyudmila V, Shatskova, Alla B, van Rijn, Clementina M
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation - adverse effects; Acute Disease; Animals; Audiogenic seizure; CB1 receptors; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoid system; Epilepsy; Epilepsy, Reflex - chemically induced; Epilepsy, Reflex - physiopathology; Kindling, Neurologic - drug effects; Kindling, Neurologic - physiology; Limbic System - drug effects; Limbic System - physiopathology; Male; Neurology; Piperidines - pharmacology; Pyrazoles - pharmacology; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - physiology; Seizures - chemically induced; Seizures - physiopathology; SR141716 (rimonabant)
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/j.eplepsyres.2011.06.007

Summary Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures. Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30 mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks. The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain.