Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus
Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus
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DOI：
10.1007/s00213-004-1836-4
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发表时间：
2004-10-01
影响因子：
3.4
通讯作者：
Stein, DJ
中科院分区：
文献类型：
--
作者：
Harvey, BH;Oosthuizen, F;Stein, DJ
理论基础：创伤后应激障碍(PTSD)患者的海马区萎缩与应激相关的糖皮质激素和谷氨酸释放有关。谷氨酸能激活一氧化氮合酶(NOS)，而γ-氨基丁酸(GABA)可抑制谷氨酸和硝酸的传递。动物研究支持一氧化氮合酶在压力中的作用。目的：我们研究了一氧化氮合酶和糖皮质激素以及抑制性和兴奋性递质在创伤后应激障碍动物模型中的作用。方法：采用放射分析、放射配基分析和高效液相色谱结合电化学检测等方法，研究了应激应激21d后SD大鼠海马区一氧化氮合酶(NOS)活性、N-甲基-D-天冬氨酸(NMDA)受体结合特性和GABA水平。选择性的iNOS和nNOS抑制剂氨基胍(50 mg/kg/d，i.p)证实了一氧化氮合酶亚型的参与，以及应激介导的皮质酮释放在一氧化氮合酶激活中的作用。7-硝基吲唑(12.5毫克/公斤/天)和类固醇合成抑制剂酮康唑(24毫克/公斤/天)，在应激程序前和应激过程中给药21天。结果：应激引起脑组织一氧化氮合酶(NOS)活性持续升高，NMDA受体密度和总GABA水平下降。氨基胍或酮康唑，而不是7-硝基吲唑或生理盐水，可阻断应激诱导的一氧化氮合酶活性。结论：应激再应激介导糖皮质激素释放激活iNOS，继而反应性下调海马神经元NMDA受体，并使抑制性GABA通路失调。NO在神经元毒性中的作用以及谷氨酸和GABA对其的调节在应激相关的海马区变性中具有重要意义。
Rationale: Stress-related glucocorticoid and glutamate release have been implicated in hippocampal atrophy evident in patients with post-traumatic stress disorder (PTSD). Glutamatergic mechanisms activate nitric oxide synthase (NOS), while gamma-amino-butyric acid (GABA) may inhibit both glutamatergic and nitrergic transmission. Animal studies support a role for NOS in stress. Objectives: We have studied the role of NOS and glucocorticoids, as well as inhibitory and excitatory transmitters, in a putative animal model of PTSD that emphasizes repeated trauma. Methods: Hippocampal NOS activity, N-methyl-D-aspartate (NMDA) receptor binding characteristics and GABA levels were studied in Sprague-Dawley rats 21 days after exposure to a stress-stress paradigm, using radiometric analysis, radioligand studies and high-performance liquid chromatography (HPLC) analysis with electrochemical detection, respectively. The NOS isoform involved, and the role of stress-mediated corticosterone release in NOS activation, was verified with the administration of selective iNOS and nNOS inhibitors, aminoguanidine (50 mg/kg/day i.p.) and 7-nitroindazole (12.5 mg/kg/day i.p.), and the steroid synthesis inhibitor, ketoconazole (24 mg/kg/day i.p.), administered for 21 days prior to and during the stress procedure. Results: Stress evoked a sustained increase in NOS activity, but reduced NMDA receptor density and total GABA levels. Aminoguanidine or ketoconazole, but not 7-nitroindazole or saline, blocked stress-induced NOS activation. Conclusions: Stress-restress-mediated glucocorticoid release activates iNOS, followed by a reactive downregulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. The role of NO in neuronal toxicity, and its regulation by glutamate and GABA has important implications in stress-related hippocampal degeneration.