College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, University of Toledo, Health Science Campus, 3000 Arlington Avenue, HEB 282G, Toledo, OH, 43614, USA.
College of Pharmacy, Department of Pharmacology and Toxicology, Taif University, Taif, Saudi Arabia.
J Mol Neurosci. 2019 Jan;67(1):1-15. doi: 10.1007/s12031-018-1194-z. Epub 2018 Nov 23.
Evidence demonstrated that the glutamatergic system is implicated in mediating relapse to several drugs of abuse, including methamphetamine (METH). Glutamate homeostasis is maintained by a number of glutamate transporters, such as glutamate transporter type 1 (GLT-1), cystine/glutamate transporter (xCT), and glutamate aspartate transporter (GLAST). In addition, group II metabotropic glutamate receptors (mGluR2/3) were found to be implicated in relapse-seeking behavior. Ample evidence showed that β-lactam antibiotics are effective in upregulating GLT-1 and xCT expression, thus improving glutamate homeostasis and attenuating relapse to drugs of abuse. In this study, we investigated the reinstatement of METH using conditioned place preference (CPP) in male alcohol-preferring (P) rats exposed to home-cage free choice ethanol drinking. Here, we tested the effect of clavulanic acid (CA), a β-lactam, on the reinstatement of METH-seeking and ethanol drinking. In addition, we examined the expression of GLT-1, xCT, and GLAST as well as metabotropic glutamate receptor (mGluR2/3) in the nucleus accumbens (NAc) shell, NAc core, and dorsomedial prefrontal cortex (dmPFC). A priming i.p. injection of METH reinstated preference in METH-paired chamber following extinction. Chronic exposure to ethanol decreased the expression of GLT-1 and xCT in the NAc shell, but not in the NAc core or dmPFC. CA treatment blocked the reinstatement of METH-seeking, decreased ethanol intake, and restored the expression of GLT-1 and xCT in the NAc shell. In addition, the expression of mGluR2/3 was increased by CA treatment in the NAc shell and dmPFC. These findings suggest that these glutamate transporters and mGluR2/3 might be potential therapeutic targets for the attenuation of reinstatement to METH-seeking.
证据表明，谷氨酸能系统参与介导多种滥用药物的复吸，包括 methamphetamine（METH）。谷氨酸的动态平衡由多种谷氨酸转运体维持，如谷氨酸转运体 1（GLT-1）、胱氨酸/谷氨酸转运体（xCT）和谷氨酸天冬氨酸转运体（GLAST）。此外，发现 II 型代谢型谷氨酸受体（mGluR2/3）参与觅药行为的复吸。大量证据表明，β-内酰胺类抗生素通过上调 GLT-1 和 xCT 的表达，改善谷氨酸的动态平衡，从而减轻滥用药物的复吸。在这项研究中，我们使用雄性酒精偏好（P）大鼠的条件性位置偏爱（CPP）模型，研究了 METH 的复吸。在该模型中，大鼠暴露于笼内自由选择乙醇摄入环境。在此，我们测试了β-内酰胺类抗生素克拉维酸（CA）对 METH 觅药和乙醇摄入复吸的影响。此外，我们还检测了核壳accumbens（NAc）、核心 NAc 和背侧前额叶皮层（dmPFC）中谷氨酸转运体（GLT-1、xCT 和 GLAST）以及代谢型谷氨酸受体（mGluR2/3）的表达。METH 的诱导 i.p. 注射在消退后恢复了 METH 配对室的偏好。慢性乙醇暴露降低了 NAc 壳中 GLT-1 和 xCT 的表达，但在 NAc 核心或 dmPFC 中没有。CA 处理阻断了 METH 觅药的复吸，减少了乙醇摄入，并恢复了 NAc 壳中 GLT-1 和 xCT 的表达。此外，CA 处理增加了 NAc 壳和 dmPFC 中 mGluR2/3 的表达。这些发现表明，这些谷氨酸转运体和 mGluR2/3 可能是减轻 METH 觅药复吸的潜在治疗靶点。
