Xi Zheng-Xiong, Shen Hui, Baker David A, Kalivas Peter W
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
J Neurochem. 2003 Dec;87(5):1204-12. doi: 10.1046/j.1471-4159.2003.02093.x.
Previous in vitro studies have shown that group III metabotropic glutamate receptors (mGluRs) regulate synaptic glutamate release. The present study used microdialysis to characterize this regulation in vivo in rat nucleus accumbens. Reverse dialysis of the group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (L-AP4) decreased, whereas the antagonist (R,S)-alpha-methylserine-O-phosphate (MSOP) increased the extracellular level of glutamate. The decrease by L-AP4 or the increase by MSOP was antagonized by co-administration of MSOP or L-AP4, respectively. Activation of mGluR4a by (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid or mGluR6 by 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid had no effect on extracellular glutamate. (R,S)-4-Phosphonophenylglycine (PPG), another group III agonist with high affinity for mGluR4/6/8, reduced extracellular glutamate only at high concentrations capable of binding to mGluR7. The increase in extracellular glutamate by MSOP was tetrodotoxin-independent, and resistant to both the L-type and N-type Ca2+ channel blockers. L-AP4 failed to block 30 mm K+-induced vesicular glutamate release. Blockade of glutamate uptake by d,l-threo-beta-benzyloxyaspartate caused a Ca2+-independent elevation in extracellular glutamate that was reversed by L-AP4. Finally, (S)-4-carboxyphenylglycine, an inhibitor of cystine-glutamate antiporters, attenuated the L-AP4-induced reduction in extracellular glutamate. Together, these data indicate that group III mGluRs regulate in vivo extracellular glutamate in the nucleus accumbens by inhibiting non-vesicular glutamate release.
先前的体外研究表明，Ⅲ型代谢型谷氨酸受体（mGluRs）可调节突触谷氨酸释放。本研究采用微透析技术在大鼠伏隔核中对这种调节进行体内特征分析。Ⅲ型mGluR激动剂L-(+)-2-氨基-4-膦酰丁酸（L-AP4）的反向透析降低了细胞外谷氨酸水平，而拮抗剂（R,S）-α-甲基丝氨酸-O-磷酸（MSOP）则提高了细胞外谷氨酸水平。L-AP4引起的降低或MSOP引起的升高分别被共同给予MSOP或L-AP4所拮抗。(1S,3R,4S)-1-氨基环戊烷-1,2,4-三羧酸激活mGluR4a或2-氨基-4-(3-羟基-5-甲基异恶唑-4-基)丁酸激活mGluR6对细胞外谷氨酸无影响。(R,S)-4-膦酰苯甘氨酸（PPG）是另一种对mGluR4/6/8具有高亲和力的Ⅲ型激动剂，仅在能够结合mGluR7的高浓度下才降低细胞外谷氨酸。MSOP引起的细胞外谷氨酸升高与河豚毒素无关，并且对L型和N型Ca2+通道阻滞剂均有抗性。L-AP4未能阻断30 mM K+诱导的囊泡谷氨酸释放。d,l-苏式-β-苄氧基天冬氨酸对谷氨酸摄取的阻断导致细胞外谷氨酸的Ca2+非依赖性升高，L-AP4可使其逆转。最后，胱氨酸-谷氨酸反向转运体抑制剂(S)-4-羧基苯甘氨酸减弱了L-AP4诱导的细胞外谷氨酸降低。总之，这些数据表明Ⅲ型mGluRs通过抑制非囊泡性谷氨酸释放来调节伏隔核中的体内细胞外谷氨酸。
