Endocannabinoids (eCBs) and serotonin (5-HT) play a neuromodulatory role in the central
nervous system. Both eCBs and 5-HT regulate neuronal excitability and their pharmacological
potentiation has been shown to control seizures in pre-clinical and human studies.
Compelling evidence indicates that eCB and 5-HT systems interact to modulate several
physiological and pathological brain functions, such as food intake, pain, drug addiction,
depression, and anxiety. Nevertheless, there is no evidence of an eCB/5-HT interaction
in experimental and human epilepsies, including status epilepticus (SE). Here, we
performed video-EEG recording in behaving rats treated with the pro-convulsant agent
pilocarpine (PILO), in order to study the effect of the activation of CB1/5-HT2 receptors
and their interaction on SE. Synthetic cannabinoid agonist WIN55,212-2 (WIN) decreased
behavioral seizure severity of PILO-induced SE at 2 mg/kg (but not at 1 and 5 mg/kg,
i.p.), while 5-HT2B/2C receptor agonist RO60-0175 (RO; 1, 3, 10 mg/kg, i.p.) was devoid
of any effect. RO 3 mg/kg was instead capable of potentiating the effect of WIN 2 mg/kg
on the Racine scale score. Surprisingly, neither WIN 2 mg/kg nor RO 3 mg/kg had any
effect on the incidence and the intensity of EEG seizures when administered alone.
However, WIN+RO co-administration reduced the incidence and the severity of EEG SE
and increased the latency to SE onset after PILO injection. WIN+RO effects were blocked
by the selective CB1R antagonist AM251 and the 5-HT2BR antagonist RS127445, but not
by the 5-HT2CR antagonist SB242084 or the 5-HT2AR antagonist MDL11,939. These data
revealed a synergistic interaction between CB1R/5-HT2BR in the expression of PILO-induced
SE.