title: Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling.
abstract: Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Chen
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Ni
authors.initials: N
authors.lastname: Fan
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Zhao-Qian
authors.initials: ZQ
authors.lastname: Teng
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Cell Biology and Anatomy, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Tang
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Song
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.|Department of Otorhinolaryngology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D002188:Cannabis / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects*
chemical_list: D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2