Llorens-Cortes C, Van Amsterdam J G, Giros B, Quach T T, Schwartz J C
Unité de Neurobiologie et Pharmacologie (U. 109) de l'INSERM, Centre Paul Broca, Paris, France.
Brain Res Mol Brain Res. 1990 Aug;8(3):227-33. doi: 10.1016/0169-328x(90)90021-5.
In order to assess changes in enkephalin release and biosynthesis, the levels of the tripeptide Tyr-Gly-Gly (YGG), a characteristic extracellular metabolite of enkephalins, and of the proenkephalin mRNA in mouse striatum were evaluated after a single administration of GABAergic agents. Significant and long-lasting decreases in steady state YGG levels were elicited by muscimol, a gamma-aminobutyric acid-A (GABAA) receptor agonist, diazepam, a benzodiazepine receptor agonist, or aminooxyacetic acid, a GABA-transaminase inhibitor. In addition, muscimol offset the elevation of striatal YGG elicited by bestatin, an aminopeptidase inhibitor, which entirely drives the released enkephalins into the metabolic pathway operated by enkephalinase (EC 3.4.24.11). Diazepam potentiated the effect of muscimol so that the YGG decrease induced by the combination of these two drugs was maximal after 30 min (-60%) and still significant (-40%) after 6 h, this potentiation being antagonized by pre-treatment with Ro 15-1788, a specific benzodiazepine receptor antagonist. By contrast [Met5]enkephalin steady-state levels were marginally affected by GABAergic agents, being only slightly reduced 6 h after the combination of muscimol and diazepam. After 3 h the same treatment also reduced by about 30% the level of proenkephalin mRNA, this change being maximal after 6 h (-45%) and still present after 24 h. These compared changes in various indexes of enkephalin neuron activity suggest that stimulation of GABAA receptors depresses enkephalin release immediately and for several hours, whereas preproenkephalin gene expression is decreased in a somewhat delayed and longer lasting manner. These patterns of temporal changes in biosynthesis and release of the neuropeptide presumably account for the limited changes in its steady state levels.
为了评估脑啡肽释放和生物合成的变化，在单次给予GABA能药物后，对小鼠纹状体中三肽酪氨酸-甘氨酸-甘氨酸（YGG）（脑啡肽的一种典型细胞外代谢产物）的水平以及前脑啡肽mRNA的水平进行了评估。γ-氨基丁酸-A（GABAA）受体激动剂蝇蕈醇、苯二氮䓬受体激动剂地西泮或GABA转氨酶抑制剂氨氧基乙酸均可引起YGG稳态水平显著且持久的降低。此外，蝇蕈醇可抵消氨肽酶抑制剂贝司他汀引起的纹状体YGG升高，贝司他汀可完全将释放的脑啡肽驱动进入由脑啡肽酶（EC 3.4.24.11）运作的代谢途径。地西泮增强了蝇蕈醇的作用，使得这两种药物联合诱导的YGG降低在30分钟后达到最大值（-60%），6小时后仍显著（-40%），这种增强作用可被特异性苯二氮䓬受体拮抗剂Ro 15-1788预处理所拮抗。相比之下，[Met5]脑啡肽稳态水平受GABA能药物的影响较小，仅在蝇蕈醇和地西泮联合使用6小时后略有降低。3小时后，相同处理还使前脑啡肽mRNA水平降低了约30%，这种变化在6小时后达到最大值（-45%），24小时后仍然存在。脑啡肽神经元活性各种指标的这些比较变化表明，刺激GABAA受体可立即并在数小时内抑制脑啡肽释放，而前脑啡肽基因表达则以某种延迟且持续时间更长的方式降低。神经肽生物合成和释放的这些时间变化模式可能解释了其稳态水平的有限变化。
