Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A1 Receptors
Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A1 Receptors
复制标题
DOI：
10.1523/jneurosci.0148-10.2010
复制
发表时间：
2010-04-07
影响因子：
5.3
通讯作者：
Liu, Jing-Gen
中科院分区：
文献类型：
--
作者：
Lu, Gang;Zhou, Qi-Xin;Liu, Jing-Gen
长期暴露于阿片类药物会损害海马长时程增强（LTP）和空间记忆，但其机制尚不清楚。鉴于众所周知的影响腺苷，一种重要的神经调节剂，对海马神经元的兴奋性和突触可塑性，我们研究了腺苷浓度的变化对慢性吗啡治疗诱导的海马CA 1 LTP和空间记忆障碍的潜在影响。我们发现，无论是增加剂量（20-100 mg/kg）的吗啡7天或相同的每日剂量（20 mg/kg）的吗啡12天的慢性治疗小鼠海马细胞外腺苷浓度显着增加。重要的是，我们发现积累的腺苷有助于抑制海马CA 1 LTP和Morris水迷宫中测量的空间记忆提取的损害。腺苷A（1）受体拮抗剂8-环戊基-1，3-二丙基黄嘌呤可显著逆转慢性吗啡诱导的海马CA 1区LTP和空间记忆障碍。同样，腺苷脱氨酶，它将腺苷转化为非活性代谢产物肌苷，恢复受损的海马CA 1 LTP。我们进一步发现，腺苷积累是由于腺苷摄取的改变，但不是腺苷代谢。双向核苷转运蛋白（ENT 2）似乎在腺苷摄取减少中起关键作用。PKC-α/β活性的变化与ENT 2功能的衰减在短期（2小时），但在长期（7天）期间终止吗啡治疗后。本研究揭示了慢性吗啡暴露导致海马LTP和空间记忆损害的潜在机制。
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.