title: CB1 agonists, locally applied to the cortico-thalamic circuit of rats with genetic absence epilepsy, reduce epileptic manifestations.
abstract: Drugs that modulate the endocannabinoid system and endocannabinoids typically play an anticonvulsant role although some proconvulsant effects have been reported both in humans and animal models. Moreover, no evidence for a role of the cannabinoid system in human absence epilepsy has been found although limited evidence of efficacy in relevant experimental animal models has been documented. This study aims to characterize the role of cannabinoids in specific areas of the cortico-thalamic network involved in oscillations that underlie seizures in a genetic animal model of absence epilepsy, the WAG/Rij rat. We assessed the effects of focal injection of the endogenous cannabinoid, anandamide (AEA), a non-selective CB receptor agonist (WIN55,212) and a selective CB1 receptor antagonist/inverse agonist (SR141716A) into thalamic nuclei and primary somatosensory cortex (S1po) of the cortico-thalamic network. AEA and WIN both reduced absence seizures independently from the brain focal site of infusion while, conversely, rimonabant increased absence seizures but only when focally administered to the ventroposteromedial thalamic nucleus (VPM). These results, together with previous reports, support therapeutic potential for endocannabinoid system modulators in absence epilepsy and highlight that attenuated endocannabinergic function may contribute to the generation and maintenance of seizures. Furthermore, the entire cortico-thalamic network responds to cannabinoid treatment, indicating that in all areas considered, CB receptor activation inhibits the pathological synchronization that subserves absence seizures. In conclusion, our result might be useful for the identification of future drug therapies in absence epilepsy.
authors.affiliation: Chair of Pharmacology, Department of Health Science, School of Medicine and Surgery, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Citraro
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.forename: Richard T
authors.initials: RT
authors.lastname: Ngomba
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Francesca
authors.initials: F
authors.lastname: Scicchitano
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Whalley
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects*; D004569:Electroencephalography / Q000187:drug effects; D063388:Endocannabinoids / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology; D004832:Epilepsy, Absence / Q000235:genetics* / Q000517:prevention & control*; D007276:Injections, Intraventricular; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D000077285:Rimonabant; D012640:Seizures / Q000503:physiopathology; D013003:Somatosensory Cortex / Q000502:physiology; D013788:Thalamus / Q000187:drug effects*
chemical_list: D000927:Anticonvulsants; D001095:Arachidonic Acids; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant; C078814:anandamide
keywords: Anandamide; CB receptors; Rimonabant; Seizure; WAG/Rij rats; WIN55,212