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-HT_2CRs), 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-HT_2C 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 CB_1/2R agonist WIN 55,212-2 (2 mg/kg, ip) counteracted PILO-induced 5-HT_2CR downregulation. Moreover, WIN 55,212-2 uncoupled PILO-induced 5-HT_2CR/NR2A and prevented NR2A^Tyr1325 phosphorylation indirectly since no 5-HT_2CR/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.