Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents

• DOI: 10.1038/srep07642
• Publication Date: 2015-01-06T10:15:18Z
• Authors: Guy Griebel; Philippe Pichat; Sandra Beeské; Thibaud Leroy; Nicolas Redon; Agnès Jacquet; Dominique Françon; Lionel Bert; Luc Even; Mati Lopez-Grancha; Tatiana Tolstykh; Fangxian Sun; Qunyan Yu; Scott Brittain; Heike Arlt; Timothy He; Bailin Zhang; Dmitri Wiederschain; Thomas Bertrand; Jacques Houtmann; Alexey Rak; François Vallée; Nadine Michot; Franck Augé; Véronique Menet; Olivier E. Bergis; Pascal George; Patrick Avenet; Vincent Mikol; Michel Didier; Johanna Escoubet
• Keywords: Anandamide; 2-Arachidonoylglycerol

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports potent covalent MAGL inhibitor, SAR127303. The compound behaves as selective and competitive inhibitor mouse human MAGL, which potently elevates hippocampal levels 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects assays inflammatory visceral pain. addition, drug alters learning performance several related to episodic, working spatial memory. Moreover, long term potentiation (LTP) CA1 synaptic transmission acetylcholine release hippocampus, two hallmarks memory function, are both decreased by Although inactive acute seizure tests, repeated administration delays acquisition decreases kindled seizures mice, indicating that slows down epileptogenesis, finding deserving further investigation evaluate potential inhibitors antiepileptics. However, observation hydrolysis blockade performance, suggests such drugs may have limited value therapeutic agents.