Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus.
The functions of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid found in the brain, remain largely unknown. Here we show that two previously unknown inhibitors of monoacylglycerol lipase, a presynaptic enzyme that hydrolyzes 2-AG, increase 2-AG levels and enhance retrograde signaling from pyramidal neurons to GABAergic terminals in the hippocampus. These results establish a role for 2-AG in synaptic plasticity and point to monoacylglycerol lipase as a possible drug target.
Makara
Judit K
JK
Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, 8. Szigony u. 43., Budapest, H-1083 Hungary.
Mor
Marco
M
Fegley
Darren
D
Szabó
Szilárd I
SI
Kathuria
Satish
S
Astarita
Giuseppe
G
Duranti
Andrea
A
Tontini
Andrea
A
Tarzia
Giorgio
G
Rivara
Silvia
S
Freund
Tamás F
TF
Piomelli
Daniele
D
D000814:Aniline Compounds; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005989:Glycerides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
D000814:Aniline Compounds; D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C514879:URB 754; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases