The cannabinoid CB2 receptor-specific agonist AM1241 increases pentylenetetrazole-induced seizure severity in Wistar rats

- Central microinfusion of a selective CB2 agonist (AM1241) increases PTZ- induced seizures in rats.
- Blockade of CB2 cannabinoid receptors prevents the proconvulsant effects of AM1241.
- Proconvulsant effects of AM1241 are mediated by CB2 receptors.

The potential efficacy of cannabinoid receptor ligands for the treatment of epilepsy remains controversial; cannabis components that act via cannabinoid type 1 (CB1) receptors produce anticonvulsant effects in animal models despite treatment with the CB receptor agonist reliably inducing convulsions in various species. Moreover, the potential role of cannabinoid receptor type 2 (CB2) to modulate seizures remains under-investigated. This study assessed the effects of the selective CB2 receptor agonist, AM1241, on pentylenetetrazole (PTZ)-induced seizures in rats. A stereotactically placed guide cannula was surgically implanted into the right lateral ventricle in adult Wistar rats which, 5-6 days later, received an acute intracerebroventricular (i.c.v.) microinfusion of AM1241 (0.01, 1 or 10 μg/2 μl or vehicle) 5 min before intraperitoneal (i.p.) injection of PTZ (70 mg/kg). Rats were observed for 30 min and the seizure severity behavior measured using a modified Racine's scale. Additional groups of rats were pretreated with a single low dose of the selective CB2 receptor antagonist, AM630 (dose 1 mg/kg; i.p.), or vehicle, 30 min prior to i.c.v. microinfusion of AM1241 (1 μg/2 μl). AM1241 administration significantly increased tonic-clonic seizure incidence and severity while also decreasing the onset of generalized seizures (AM1241 1 and 10 μg/2 μl). Pretreatment with AM630 prevented the proconvulsant effects of AM1241. This study shows, for the first time, that selective activation of CB2 receptors can increase generalized seizure susceptibility and suggests that pathological hyperexcitability phenomena can be differentially regulated by targeting CB1 and CB2 receptors.