WIN 55,212-2 Reverted Pilocarpine-Induced Status Epilepticus Early Changes of the Interaction among 5-HT2C/NMDA/CB1 Receptors in the Rat Hippocampus.

The molecular basis for temporal lobe epileptogenesis  remains poorly defined. Recent evidence shows that serotonin 2C receptors (5-HT2CRs), NR2A and NR2B subunit-containing N-methyl-d-aspartate receptors (NMDARs) and cannabinoid 1 receptors (CB1Rs) may be involved in the progression of the epileptic disorders. Moreover, CB1R activation has been reported to modulate the activity of 5-HT2C and NMDA receptors. Here, we treated Sprague-Dawley rats with the pro-convulsant agent pilocarpine (PILO) to induce status epilepticus (SE) in order to study the effect, with regards to receptor signaling and their interactions, of the preactivation of the CB1Rs on early changes that occur 24 h from the initial insult in the hippocampus. Pretreatment with the synthetic CB1/2R agonist WIN 55,212-2 (2 mg/kg, ip) counteracted PILO-induced 5-HT2CR downregulation. Moreover, WIN 55,212-2 uncoupled PILO-induced 5-HT2CR/NR2A and prevented NR2ATyr1325 phosphorylation indirectly since no 5-HT2CR/CB1R interactions were observed. WIN 55,212-2 treatment also prevented PILO-mediated impairment of CB1R/NR2B interactions and NR2B subunit internalization, suggesting a possible role of CB1R in NR2B-containing NMDAR turn over. All the effects observed in animals treated with WIN 55,212-2 were blocked by pretreatment with the selective CB1R antagonist AM251 (1 mg/kg, ip) given 45 min before PILO injection. These results, obtained in vivo in post-PILO-induced SE, provide new insights on the early cellular responses during epileptogenesis and identify new CB1R-mediated mechanisms by which cannabinoids may prevent the development of chronic epilepsy.