title: Elevation of endogenous anandamide impairs LTP, learning, and memory through CB1 receptor signaling in mice.
abstract: In rodents, many exogenous and endogenous cannabinoids, such as anandamide (AEA) and 2-arachidonyl glycerol (2-AG), have been shown to play an important role in certain hippocampal memory processes. However, the mechanisms by which endogenous AEA regulate this processes are not well understood. Here the effects of AEA on long-term potentiation (LTP), hippocampal-dependent learning and memory tasks, pERK1/2, pCaMKIV, and pCREB signaling events in both cannabinoid receptor type 1 (CB1R) wild-type (WT) and knockout (KO) mice were assessed following administration of URB597, an inhibitor of the fatty acid amide hydrolase (FAAH). Acute administration of URB597 enhanced AEA levels without affecting the levels of 2-AG or CB1R in the hippocampus and neocortex as compared to vehicle. In hippocampal slices, URB597 impaired LTP in CB1R WT but not in KO littermates. URB597 impaired object recognition, spontaneous alternation and spatial memory in the Y-maze test in CB1R WT mice but not in KO mice. Furthermore, URB597 enhanced ERK phosphorylation in WT without affecting total ERK levels in WT or KO mice. URB597 impaired CaMKIV and CREB phosphorylation in WT but not in KO mice. CB1R KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio as compared to WT littermates. Our results indicate that pharmacologically elevated AEA impair LTP, learning and memory and inhibit CaMKIV and CREB phosphorylation, via the activation of CB1Rs. Collectively, these findings also suggest that pharmacological elevation of AEA beyond normal concentrations is also detrimental for the underlying physiological responses.
authors.affiliation: Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York; New York State Psychiatric Institute, College of Physicians & Surgeons, Columbia University, New York, New York; Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, New York.
authors.forename: Balapal S
authors.initials: BS
authors.lastname: Basavarajappa
authors.forename: Nagaraja N
authors.initials: NN
authors.lastname: Nagre
authors.forename: Shan
authors.initials: S
authors.lastname: Xie
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Subbanna
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D063388:Endocannabinoids / Q000502:physiology*; D005989:Glycerides / Q000502:physiology; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D053284:Polyunsaturated Alkamides; D011499:Protein Processing, Post-Translational; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D065852:Spatial Memory / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D002219:Carbamates; D017362:Cyclic AMP Response Element-Binding Protein; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C543264:Cnr1 protein, rat; C492004:Creb1 protein, mouse; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C094503:glyceryl 2-arachidonate; C078814:anandamide
keywords: CB1 null mice; CREB; CaMKIV phosphorylation; URB597; anandamide; fatty acid amide hydrolase; long-term potentiation; mitogen-activated protein kinase