The selective iGluR1-4 (AMPA) antagonist LY300168 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioural signs of morphine withdrawal
The selective iGluR1-4 (AMPA) antagonist LY300168 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioural signs of morphine withdrawal
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DOI：
10.1016/s0028-3908(02)00296-4
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发表时间：
2003-01
影响因子：
4.7
通讯作者：
K. Rasmussen;Jim L. Vandergriff
中科院分区：
文献类型：
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作者：
K. Rasmussen;Jim L. Vandergriff
之前，我们已经证明AMPA （iGluR1-4）拮抗剂LY293558减弱吗啡戒断诱导的蓝斑神经元激活和吗啡戒断的行为体征。然而，LY293558已被证明对一种类型的盐酸盐受体（iGluR5）也有亲和力。在这项研究中，我们检测了iGluR1-4受体的选择性拮抗剂LY300168 （GYKI 53655）和iGluR5受体的选择性拮抗剂LY382884对吗啡戒断诱导的蓝斑神经元激活和吗啡戒断行为体征的影响。在麻醉大鼠的体内记录中，LY300168 （0.3-3.0 mg/kg, s.c）预处理，而LY382884（已知有中枢效应的剂量，100mg /kg, s.c）没有减弱吗啡戒断诱导的LC神经元激活。在未麻醉的吗啡依赖大鼠中，LY300168 （0.3-3.0 mg/kg, s.c）预处理，而LY382884 （100 mg/kg, s.c）没有抑制纳曲酮沉淀的吗啡戒断症状的严重程度和发生。这些结果表明，iGluR1-4 （AMPA）受体，而不是iGluR5受体，在吗啡戒断诱导的LC神经元激活和吗啡戒断的一部分行为体征中起重要作用。此外，选择性AMPA拮抗剂可用于治疗阿片类药物和其他滥用药物的戒断。
Previously, we have shown that the AMPA (iGluR1-4) antagonist LY293558 attenuates the morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. However, LY293558 has since been shown to also have affinity for one subtype of kainate receptor (iGluR5). In this study, we examined the effects of a selective antagonist of iGluR1-4 receptors, LY300168 (GYKI 53655), and a selective antagonist of iGluR5 receptors, LY382884, on the morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY300168 (0.3–3.0 mg/kg, s.c.), but not LY382884 (at a dose known to have central effects; 100 mg/kg, s.c.) attenuated the morphine-withdrawal-induced activation of LC neurons. In unanesthetized, morphine-dependent rats, pretreatment with LY300168 (0.3–3.0 mg/kg, s.c.), but not LY382884 (100 mg/kg, s.c.), suppressed the severity and occurrence of naltrexone-precipitated morphine-withdrawal signs. These results indicate iGluR1-4 (AMPA) receptors, but not iGluR5 receptors, play an important role the morphine-withdrawal-induced activation of LC neurons and a subset of behavioral signs of morphine withdrawal. In addition, selective AMPA antagonists may have therapeutic effects in man for the treatment of withdrawal from opiates and other drugs of abuse.