The Solomon H. Snyder Department of Neuroscience and Departments of Pharmacology and Molecular Sciences and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
Neuropharmacology. 2014 Feb;77:28-38. doi: 10.1016/j.neuropharm.2013.08.036. Epub 2013 Sep 10.
Behavioral sensitization to cocaine is associated with increased AMPA receptor (AMPAR) surface expression in the nucleus accumbens (NAc). This upregulation is withdrawal-dependent, as it is not detected on withdrawal day (WD) 1, but is observed on WD7-21. Its underlying mechanisms have not been clearly established. Nitric oxide (NO) regulates AMPAR trafficking in the brain by S-nitrosylation of the AMPAR auxiliary subunit, stargazin, leading to increased AMPAR surface expression. Our goal was to determine if stargazin S-nitrosylation contributes to AMPAR upregulation during sensitization. First, we measured stargazin S-nitrosylation in NAc core and shell subregions on WD14 after 8 daily injections of saline or 15 mg/kg cocaine. Stargazin S-nitrosylation was markedly increased in NAc shell but not core. To determine if this is associated with AMPAR upregulation, rats received 8 cocaine or saline injections followed by twice-daily treatments with vehicle or the nitric oxide synthase inhibitor l-NAME (50 mg/kg) on WD1-6, the time when AMPAR upregulation is developing in cocaine-exposed rats. Cocaine/vehicle rats showed elevated stargazin and GluA1 surface expression on WD7 compared to saline/vehicle rats; the GluA1 increase was more robust in core, while stargazin increased more robustly in shell. These effects of cocaine were attenuated in shell but not core when cocaine injections were followed by l-NAME treatment on WD1-6. Together, these results indicate that elevated S-nitrosylation of stargazin contributes to AMPAR upregulation during sensitization selectively in the NAc shell. It is possible that AMPAR upregulation in core involves a different TARP, γ4, which also upregulates in the NAc of sensitized rats.
可卡因诱导的行为敏化与伏隔核（NAc）中 AMPA 受体（AMPAR）表面表达增加有关。这种上调是依赖于戒断的，因为在戒断第 1 天（WD）1 时没有检测到，而是在 WD7-21 时观察到。其潜在机制尚未明确。一氧化氮（NO）通过 AMPAR 辅助亚基星状蛋白的 S-亚硝基化调节大脑中的 AMPAR 转运，导致 AMPAR 表面表达增加。我们的目标是确定星状蛋白 S-亚硝基化是否有助于敏化过程中 AMPAR 的上调。首先，我们在 8 次每日生理盐水或 15mg/kg 可卡因注射后 WD14 时测量了 NAc 核心和壳区中亚基的 S-亚硝基化。星状蛋白 S-亚硝基化在 NAc 壳区显著增加，但在核心区没有增加。为了确定这是否与 AMPAR 上调有关，大鼠接受 8 次可卡因或生理盐水注射，然后在 WD1-6 期间每日两次接受 vehicle 或一氧化氮合酶抑制剂 l-NAME（50mg/kg）治疗，此时可卡因暴露大鼠的 AMPAR 上调正在发展。与生理盐水/vehicle 大鼠相比，可卡因/vehicle 大鼠在 WD7 时显示出星状蛋白和 GluA1 表面表达升高；在核心区，GluA1 增加更明显，而在壳区，星状蛋白增加更明显。当可卡因注射后在 WD1-6 期间用 l-NAME 处理时，可卡因在壳区但不在核心区的这些作用减弱。综上所述，这些结果表明，在敏化过程中，星状蛋白的 S-亚硝基化升高有助于选择性地在 NAc 壳区上调 AMPAR。在敏化大鼠的 NAc 中，可能涉及不同的 TARP γ4，它也会上调，这也会导致 AMPAR 上调。
