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Neurobiol Dis. 2019 May;125:135-145. doi: 10.1016/j.nbd.2019.01.026. Epub 2019 Feb 1.

Synergistic action of CB1 and 5-HT2B receptors in preventing pilocarpine-induced status epilepticus in rats.

Author information

1
Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta. Electronic address: roberto.colangeli@ucalgary.ca.
2
Pittsburgh Inst. for Neurodegenerative Dis., Dept. of Neurology, Univ. of Pittsburgh, PA, USA.
3
Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
4
Department of Experimental Biomedicine and Clinical Neurosciences, Human Physiology Section "Giuseppe Pagano", University of Palermo, Palermo, Italy.
5
Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; School of Biosciences, Cardiff University, Cardiff, UK. Electronic address: giuseppe.digiovanni@um.edu.mt.

Abstract

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.

KEYWORDS:

Cannabinoid receptors; Clinical applications; EEG; Endocannabinoid system; Serotonin; Status epilepticus; Synergistic interactions

PMID:
30716469
DOI:
10.1016/j.nbd.2019.01.026

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