title: CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations.
abstract: Recently, synthetic cannabinoids have been sprayed onto plant material, which is subsequently packaged and sold as "Spice" or "K2" to mimic the effects of marijuana. A recent report identified several synthetic additives in samples of "Spice/K2", including JWH-081, a synthetic ligand for the cannabinoid receptor 1 (CB1). The deleterious effects of JWH-081 on brain function are not known, particularly on CB1 signaling, synaptic plasticity, learning and memory. Here, we evaluated the effects of JWH-081 on pCaMKIV, pCREB, and pERK1/2 signaling events followed by long-term potentiation (LTP), hippocampal-dependent learning and memory tasks using CB1 receptor wild-type (WT) and knockout (KO) mice. Acute administration of JWH-081 impaired CaMKIV phosphorylation in a dose-dependent manner, whereas inhibition of CREB phosphorylation in CB1 receptor WT mice was observed only at higher dose of JWH-081 (1.25 mg/kg). JWH-081 at higher dose impaired CaMKIV and CREB phosphorylation in a time-dependent manner in CB1 receptor WT mice but not in KO mice and failed to alter ERK1/2 phosphorylation. In addition, SR treated or CB1 receptor KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio compared with vehicle or WT littermates. In hippocampal slices, JWH-081 impaired LTP in CB1 receptor WT but not in KO littermates. Furthermore, JWH-081 at higher dose impaired object recognition, spontaneous alternation and spatial memory on the Y-maze in CB1 receptor WT mice but not in KO mice. Collectively our findings suggest that deleterious effects of JWH-081 on hippocampal function involves CB1 receptor mediated impairments in CaMKIV and CREB phosphorylation, LTP, learning and memory in mice.
authors.forename: Balapal S
authors.initials: BS
authors.lastname: Basavarajappa
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Subbanna
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002186:Cannabinoids / Q000737:chemistry* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007211:Indoles / Q000494:pharmacology / Q000633:toxicity; D007859:Learning Disabilities / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D017774:Long-Term Potentiation / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects; D013028:Space Perception / Q000187:drug effects; D013569:Synapses / Q000187:drug effects
chemical_list: C000591713:(4-methoxy-1-naphthalenyl)(1-pentyl-1H-indol-3-yl)methanone; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D007211:Indoles; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050882:CREB-Binding Protein; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; D000077285:Rimonabant