Department of Neuroscience, The Chicago Medical School at Rosalind Franklin School of Medicine and Science, North Chicago, Illinois.
Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, Georgia.
Biol Psychiatry. 2018 Aug 1;84(3):223-232. doi: 10.1016/j.biopsych.2018.02.012. Epub 2018 Feb 23.
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.
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 S-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.
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.
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.
在可卡因自我给药戒除期间，线索诱导的可卡因渴望会逐渐形成。这种潜伏期的表达最终取决于伏隔核（NAc）中同源 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。异常的翻译与中枢神经系统疾病有关，但在药物-naive NAc 或潜伏期后，谷氨酸能调节翻译的情况尚不清楚。
从药物-naive 大鼠和经过 1 天或 >40 天戒除延长可卡因或盐水自我给药的大鼠中获得 NAc 组织。使用 S-Met/Cys 或嘌呤霉素标记新翻译的蛋白质。我们比较了药物-naive、盐水对照和可卡因大鼠中代谢型谷氨酸受体 1 (mGlu1)、mGlu5 和 N-甲基-D-天冬氨酸受体 (NMDAR) 对基础总翻译的调节作用，并且我们通过免疫沉淀嘌呤霉素标记的蛋白质比较了 GluA1 和 GluA2 的翻译。
在所有组中，mGlu1 阻断（LY367385）均未改变总翻译，但 mGlu5 阻断（MTEP）增加了总翻译。NMDAR 阻断（AVP）增加了药物-naive 和盐水对照大鼠的总翻译，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高的 GluA1 翻译（但不是 GluA2），而 NMDAR 阻断对其没有进一步影响。
我们的结果表明，增加的 GluA1 翻译有助于介导潜伏期的 NAc 中升高的同源 GluA1 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体水平。与潜伏期相关的可塑性的其他贡献可能来自于 NMDAR 对翻译的正常制动作用的丧失。除了阐明与潜伏期相关的适应外，我们还发现 mGlu5 对 NAc 翻译具有抑制作用，无论是否暴露于药物，这与在海马体中获得的结果相反，表明不同脑区之间的翻译调节存在异质性。
