Zhong Weixia, Dong Zhifang, Tian Meng, Cao Jun, Xu Tianle, Xu Lin, Luo Jianhong
Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou 310006, PR China.
Life Sci. 2006 Jul 24;79(9):861-9. doi: 10.1016/j.lfs.2006.02.040. Epub 2006 Mar 21.
Adaptive changes in brain areas following drug withdrawal are believed to contribute to drug seeking and relapse. Cocaine withdrawal alters the expression of GluR1 and GluR2/3 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in nucleus accumbens or amygdala, but the influence of drug withdrawal on hippocampus is little known. Here, we have examined the expression of GluR1 and GluR2/3 in hippocampal membrane and synaptic fractions following repeated morphine exposure and subsequent withdrawal. Repeated morphine exposure for 12 d increased GluR1 and GluR2/3 in synaptosome but not in membrane fraction. Interestingly, CaMKIIalpha, known to be able to regulate the function of AMPA receptors, was decreased in synaptosome but not in membrane fraction; pCaMKIIalpha, the phosphorylated form of CaMKIIalpha, was increased in both fractions. However, during opiate withdrawal, GluR1 was generally reduced while GluR2/3 was prominently increased in both fractions; pCaMKIIalpha was strongly decreased immediately after withdrawal, but detectably increased in late phase of morphine withdrawal in both fractions. Importantly, the opiate withdrawal-induced increase in GluR2/3 was dependent on the activation of glucocorticoid receptors and NMDA receptors, as it was prevented by the glucocorticoid receptor antagonist RU38486, or intrahippocampal injection of the NMDA receptor antagonist AP-5 or the antagonist to NR2B-containing NMDA receptors, Ro25-6981. These findings indicate that opiate withdrawal induces dynamic expression of GluR1 and GluR2/3 subunits of AMPA receptors in hippocampal synapses, possibly revealing an adaptive process of the hippocampal functions following opiate withdrawal.
药物戒断后大脑区域的适应性变化被认为会导致觅药行为和复吸。可卡因戒断会改变伏隔核或杏仁核中α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体的GluR1和GluR2/3亚基的表达，但药物戒断对海马体的影响却鲜为人知。在此，我们检测了反复暴露于吗啡并随后戒断后海马体膜和突触组分中GluR1和GluR2/3的表达。反复暴露于吗啡12天会增加突触体中GluR1和GluR2/3的表达，但不会增加膜组分中的表达。有趣的是，已知能够调节AMPA受体功能的CaMKIIα在突触体中减少，但在膜组分中未减少；CaMKIIα的磷酸化形式pCaMKIIα在两个组分中均增加。然而，在阿片类药物戒断期间，两个组分中的GluR1总体上减少，而GluR2/3显著增加；pCaMKIIα在戒断后立即大幅减少，但在吗啡戒断后期两个组分中均可检测到增加。重要的是，阿片类药物戒断诱导的GluR2/3增加依赖于糖皮质激素受体和NMDA受体的激活，因为糖皮质激素受体拮抗剂RU38486、海马体内注射NMDA受体拮抗剂AP-5或含NR2B的NMDA受体拮抗剂Ro25-6981均可阻止这种增加。这些发现表明，阿片类药物戒断会诱导海马体突触中AMPA受体的GluR1和GluR2/3亚基的动态表达，这可能揭示了阿片类药物戒断后海马体功能的适应性过程。
