Inhibition of PKMzeta in nucleus accumbens core abolishes long-term drug reward memory.
Inhibition of PKMzeta in nucleus accumbens core abolishes long-term drug reward memory.
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DOI：
10.1523/jneurosci.5884-10.2011
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发表时间：
2011-04-06
期刊：
影响因子：
--
通讯作者：
Lu L
中科院分区：
文献类型：
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作者：
Li YQ;Xue YX;He YY;Li FQ;Xue LF;Xu CM;Sacktor TC;Shaham Y;Lu L
在戒毒期间，对与药物有关的线索的记忆会持续数月，而接触这些线索往往会引发吸毒复发。维持这些记忆的潜在机制尚不清楚。在维持空间记忆、条件性味觉厌恶和其他记忆形式中，需要一种具有结构性活性的非典型蛋白激酶C同工酶，即蛋白激酶Mζ(PKMζ)。采用条件性位置偏爱和条件性位置厌恶方法，研究伏隔核PKMζ在维持大鼠药物奖赏和厌恶记忆中的作用。吗啡CPP训练(10 mg/kg，4对)可增加伏隔核中PKMζ的表达，但不能增加其外壳中PKM的表达。在CPP训练后，将PKMζ抑制剂ζ抑制肽(ZIP)注入伏隔核而不是壳层，可阻断吗啡CPP的表达，持续时间长达14d。这种作用可被抑制PKMζ的蛋白激酶C抑制剂白屈菜红碱所模拟，但不能被常规和新型的蛋白激酶C抑制剂星形孢子素所模拟，后者不能有效地抑制PKMζ。训练结束后，伏隔核内注射Zip也可阻断可卡因(10 mg/kg)和高脂食物CPP的表达，但对纳洛酮催促的吗啡戒断所致的CPA无影响。伏隔核注射抑制GluR2依赖的AMPA受体内吞的TAT-GluR23Y，可拮抗局部注射ZIP对吗啡CPP的损伤作用，提示PKMζ的持续作用是在含GluR2的AMPA受体上实现的。结果表明，伏隔核的PKMζ活性是在长时间戒断期间维持对诱发复发的奖赏线索的记忆的关键细胞底物。
During abstinence, memories of drug-associated cues persist for many months, and exposure to these cues often provokes relapse to drug use. The mechanisms underlying the maintenance of these memories are unknown. A constitutively active atypical protein kinase C (PKC) isozyme, protein kinase M ζ (PKMζ), is required for maintenance of spatial memory, conditioned taste aversion, and other memory forms. We used conditioned place preference (CPP) and conditioned place aversion (CPA) procedures to study the role of nucleus accumbens PKMζ in the maintenance of drug reward and aversion memories in rats. Morphine CPP training (10 mg/kg, 4 pairings) increased PKMζ levels in accumbens core but not shell. Injections of the PKMζ inhibitor ζ inhibitory peptide (ZIP) into accumbens core but not shell after CPP training blocked morphine CPP expression for up to 14 d after injections. This effect was mimicked by the PKC inhibitor chelerythrine, which inhibits PKMζ, but not by the conventional and novel PKC inhibitor staurosporine, which does not effectively inhibit PKMζ. ZIP injections into accumbens core after training also blocked the expression of cocaine (10 mg/kg) and high-fat food CPP but had no effect on CPA induced by naloxone-precipitated morphine withdrawal. Accumbens core injections of Tat-GluR23Y, which inhibits GluR2-dependent AMPA receptor endocytosis, prevented the impairment in morphine CPP induced by local ZIP injections, indicating that the persistent effect of PKMζ is on GluR2-containing AMPA receptors. Results indicate that PKMζ activity in accumbens core is a critical cellular substrate for the maintenance of memories of relapse-provoking reward cues during prolonged abstinence periods.