Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A1 Receptors

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 investigate...

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Bibliographic Details
Published in:The Journal of neuroscience 2010-04, Vol.30 (14), p.5058-5070
Main Authors: Lu, Gang, Zhou, Qi-Xin, Kang, Shuo, Li, Qing-Lin, Zhao, Liang-Cai, Chen, Jia-Dong, Sun, Jian-Feng, Cao, Jun, Wang, Yu-Jun, Chen, Jie, Chen, Xiao-Yan, Zhong, Da-Fang, Chi, Zhi-Qiang, Xu, Lin, Liu, Jing-Gen
Format: Article
Language:English
Subjects:
Adenosine - metabolism
Adenosine - toxicity
Adenosine A1 Receptor Agonists
Animals
Drug Administration Schedule
Extracellular Space - drug effects
Extracellular Space - metabolism
Hippocampus - drug effects
Hippocampus - metabolism
Long-Term Potentiation - drug effects
Long-Term Potentiation - physiology
Male
Maze Learning - drug effects
Maze Learning - physiology
Memory - drug effects
Memory - physiology
Mice
Morphine - administration & dosage
Morphine - toxicity
Receptor, Adenosine A1 - metabolism
Spatial Behavior - drug effects
Spatial Behavior - physiology
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0148-10.2010