Patte C, Gandolfo P, Leprince J, Thoumas J L, Fontaine M, Vaudry H, Tonon M C
European Institute for Peptide Research (IFRMP no 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U 413, UA CNRS, University of Rouen, Mont-Saint-Aignan, France.
Glia. 1999 Feb 15;25(4):404-11.
In the mammalian brain, the endogenous ligands for benzodiazepine receptors (also called endozepines) are predominantly synthesized by glial cells. It has recently been reported that rat astrocytes in primary culture release substantial amounts of endozepines. The aim of the present study was to investigate the possible involvement of GABA in the control of endozepine release. Exposure of cultured rat astrocytes to GABA (10(-7) to 10(-5) M) induced a dose-related inhibition of endozepine secretion. At higher doses (3 x 10(-5) to 10(-3) M), the effect of GABA gradually diminished. The inhibitory effect of GABA (10(-5) M) was mimicked by the GABA(B) receptor agonist baclofen (10(-5) M). In contrast, the GABA(A) receptor agonists 3APS and isoguvacine (10(-5) M each) did not modify endozepine release. The inhibition of endozepine secretion evoked by GABA and baclofen (10(-5) M each) was totally abrogated by the specific GABA(B) receptor antagonist phaclofen (10(-4) M). GABA and baclofen caused a significant inhibition of forskolin-evoked production of cAMP in astrocytes and this effect was abolished in the presence of phaclofen. In contrast, isoguvacine had no effect on cAMP production. Exposure of astrocytes to dbcAMP induced a time- and dose-dependent stimulation of endozepine release. These data indicate that GABA, acting through GABA(B) receptors negatively coupled to adenylyl cyclase, inhibits endozepine release from cultured rat astrocytes. The secretion of endozepines thus appears to be a valuable marker to monitor astrocyte activity.
在哺乳动物大脑中，苯二氮䓬受体的内源性配体（也称为内源性苯二氮䓬）主要由神经胶质细胞合成。最近有报道称，原代培养的大鼠星形胶质细胞会释放大量内源性苯二氮䓬。本研究的目的是探讨γ-氨基丁酸（GABA）在控制内源性苯二氮䓬释放中可能发挥的作用。将培养的大鼠星形胶质细胞暴露于GABA（10⁻⁷至10⁻⁵M）会诱导内源性苯二氮䓬分泌呈剂量依赖性抑制。在较高剂量（3×10⁻⁵至10⁻³M）时，GABA的作用逐渐减弱。GABA（10⁻⁵M）的抑制作用可被GABA(B)受体激动剂巴氯芬（10⁻⁵M）模拟。相比之下，GABA(A)受体激动剂3-氨基丙磺酸（3APS）和异谷氨酰胺（各10⁻⁵M）并未改变内源性苯二氮䓬的释放。GABA和巴氯芬（各10⁻⁵M）引起的内源性苯二氮䓬分泌抑制被特异性GABA(B)受体拮抗剂法氯芬（10⁻⁴M）完全消除。GABA和巴氯芬对星形胶质细胞中福斯高林诱发的环磷酸腺苷（cAMP）生成有显著抑制作用，且在法氯芬存在时这种作用被消除。相比之下，异谷氨酰胺对cAMP生成没有影响。将星形胶质细胞暴露于二丁酰环磷腺苷（dbcAMP）会诱导内源性苯二氮䓬释放呈时间和剂量依赖性刺激。这些数据表明，GABA通过与腺苷酸环化酶负偶联的GABA(B)受体发挥作用，抑制培养的大鼠星形胶质细胞释放内源性苯二氮䓬。因此，内源性苯二氮䓬的分泌似乎是监测星形胶质细胞活性的一个有价值的指标。
