title: Chronic morphine treatment impaired hippocampal long-term potentiation and spatial memory via accumulation of extracellular adenosine acting on adenosine A1 receptors.
abstract: Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20-100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-alpha/beta activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute For Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China. jgliu@mail.shcnc.ac.cn
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Qi-Xin
authors.initials: QX
authors.lastname: Zhou
authors.forename: Shuo
authors.initials: S
authors.lastname: Kang
authors.forename: Qing-Lin
authors.initials: QL
authors.lastname: Li
authors.forename: Liang-Cai
authors.initials: LC
authors.lastname: Zhao
authors.forename: Jia-Dong
authors.initials: JD
authors.lastname: Chen
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chen
authors.forename: Da-Fang
authors.initials: DF
authors.lastname: Zhong
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Chi
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Jing-Gen
authors.initials: JG
authors.lastname: Liu
mesh_terms: D000241:Adenosine / Q000378:metabolism* / Q000633:toxicity; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D004334:Drug Administration Schedule; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000633:toxicity; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D009020:Morphine; D000241:Adenosine