Department of Clinical and Experimental Medicine, Pharmacology Section and LTTA Centre, University of Ferrara, Via Fossato di Mortara 17-19, 44100, Ferrara, Italy.
Pharmacol Rep. 2011;63(6):1359-71. doi: 10.1016/s1734-1140(11)70700-9.
In the present study, the effects of the γ-hydroxybutyrate (GHB) analog GET73 on hippocampal glutamate transmission have been evaluated by an approach combining in vivo microdialysis with the in vitro evaluation of tissue slices. The microdialysis results indicated that local perfusion (60 min) with 10 nM - 1mM GET73 increased extracellular glutamate levels in the CA1 region of the hippocampus of freely moving rats in a concentration dependent manner. In tissue slices from the rat hippocampus, GET73 (1 μM - 10 μM) did not affect L-[(3)H]glutamate uptake, whereas treatment with 1 μM GET73 significantly increased K(+)-evoked, but not spontaneous, glutamate efflux. The GHB analog did not affect the increase in glutamate efflux induced by 100 μM and 300 μM NMDA. In contrast, 500 nM GET73, a concentration at which it is ineffective alone, partially but significantly counteracted the increase in K(+)-evoked glutamate efflux induced by 100 μM CHPG, an mGluR5 agonist. When 500 nM GET73 was coperfused with 100 μM MPEP, it amplified the decrease in K(+)-evoked glutamate efflux induced by the mGluR5 antagonist. Interestingly, the increase in K(+)-evoked glutamate efflux induced by 1 μM GET73 was counteracted by coperfusion with a low (10 μM) concentration of MPEP, which by itself is ineffective. Finally, 500 nM GET73 did not affect the reduction of K(+)-evoked glutamate efflux induced by the mGluR2/3 agonist LY379268. These findings demonstrate that the GHB analog GET73 significantly affects glutamate transmission in the hippocampus, and its profile of action differs from that of its parent compound.
在本研究中，通过将体内微透析与体外组织切片评估相结合的方法，评估了γ-羟基丁酸（GHB）类似物 GET73 对海马谷氨酸传递的影响。微透析结果表明，局部灌流（60 分钟）10 nM-1mM GET73 以浓度依赖的方式增加了自由移动大鼠海马 CA1 区细胞外谷氨酸水平。在来自大鼠海马的组织切片中，GET73（1 μM-10 μM）不影响 L-[(3)H]谷氨酸摄取，而用 1 μM GET73 处理则显著增加了 K(+)-诱发的谷氨酸外排，但不影响自发的谷氨酸外排。GHB 类似物不影响 100 μM 和 300 μM NMDA 诱导的谷氨酸外排增加。相比之下，500 nM GET73，一种单独使用时无效的浓度，部分但显著地对抗了 100 μM CHPG（mGluR5 激动剂）诱导的 K(+)-诱发谷氨酸外排的增加。当 500 nM GET73 与 100 μM MPEP 共灌流时，它放大了 mGluR5 拮抗剂诱导的 K(+)-诱发谷氨酸外排的减少。有趣的是，1 μM GET73 诱导的 K(+)-诱发谷氨酸外排的增加被低浓度（10 μM）MPEP 共灌流所对抗，而单独使用 MPEP 则无效。最后，500 nM GET73 不影响 mGluR2/3 激动剂 LY379268 诱导的 K(+)-诱发谷氨酸外排的减少。这些发现表明，GHB 类似物 GET73 显著影响海马中的谷氨酸传递，其作用模式与其母体化合物不同。
