BACKGROUND Cue-induced cocaine craving incubates during abstinence from cocaine self-administration. Expression of incubation ultimately depends on elevation of homomeric GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in the nucleus accumbens (NAc). This adaptation requires ongoing protein translation for its maintenance. Aberrant translation is implicated in central nervous system diseases, but nothing is known about glutamatergic regulation of translation in the drug-naïve NAc or after incubation. METHODS NAc tissue was obtained from drug-naïve rats and from rats after 1 or >40 days of abstinence from extended-access cocaine or saline self-administration. Newly translated proteins were labeled using 35S-Met/Cys or puromycin. We compared basal overall translation and its regulation by metabotropic glutamate receptor 1 (mGlu1), mGlu5, and N-methyl-D-aspartate receptors (NMDARs) in drug-naïve, saline control, and cocaine rats, and we compared GluA1 and GluA2 translation by immunoprecipitating puromycin-labeled proteins. RESULTS In all groups, overall translation was unaltered by mGlu1 blockade (LY367385) but increased by mGlu5 blockade (MTEP). NMDAR blockade (AVP) increased overall translation in drug-naïve and saline control rats but not in cocaine/late withdrawal rats. Cocaine/late withdrawal rats exhibited greater translation of GluA1 (but not GluA2), which was not further affected by NMDAR blockade. CONCLUSIONS Our results suggest that increased GluA1 translation contributes to the elevated homomeric GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor levels in the NAc that mediate incubation. Additional contributions to incubation-related plasticity may result from loss of the braking influence on translation normally exerted by NMDARs. Apart from elucidating incubation-related adaptations, we found a suppressive effect of mGlu5 on NAc translation regardless of drug exposure, which is opposite to results obtained in the hippocampus and points to heterogeneity of translational regulation between brain regions.

中文翻译：

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戒断可卡因自我给药改变了伏隔核中蛋白质翻译的调节

背景提示诱导的可卡因渴望在可卡因自我给药的戒断期间孵化。孵化的表达最终取决于伏核 (NAc) 中同聚 GluA1 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的升高。这种适应需要持续的蛋白质翻译来维持。异常翻译与中枢神经系统疾病有关，但在未使用药物的 NAc 中或孵育后对翻译的谷氨酸能调节一无所知。方法 NAc 组织来自未使用药物的大鼠和禁欲 1 天或 >40 天后的大鼠，其中包括长期使用可卡因或生理盐水的自我给药。使用 35S-Met/Cys 或嘌呤霉素标记新翻译的蛋白质。我们比较了基础的整体翻译及其通过代谢型谷氨酸受体 1 (mGlu1)、mGlu5 和 N-甲基-D-天冬氨酸受体 (NMDAR) 在未用药、盐水对照和可卡因大鼠中的调节，并比较了 GluA1 和 GluA2 的翻译通过免疫沉淀嘌呤霉素标记的蛋白质。结果 在所有组中，mGlu1 阻断 (LY367385) 未改变整体翻译，但 mGlu5 阻断 (MTEP) 增加了翻译。NMDAR 阻断剂 (AVP) 增加了未使用药物和盐水对照大鼠的整体翻译，但在可卡因/晚期戒断大鼠中没有增加。可卡因/晚期戒断大鼠表现出更大的 GluA1（但不是 GluA2）的翻译，这不受 NMDAR 封锁的进一步影响。结论我们的结果表明，增加的 GluA1 翻译有助于提高 NAc 中的同聚 GluA1 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体水平，介导孵育。对孵化相关可塑性的额外贡献可能是由于 NMDAR 通常对翻译产生的制动影响的丧失。除了阐明与孵化相关的适应性外，我们发现 mGlu5 对 NAc 翻译的抑制作用与药物暴露无关，这与在海马体中获得的结果相反，并指出大脑区域之间翻译调节的异质性。