Effects of Clavulanic Acid Treatment on Reinstatement to Methamphetamine, Glial Glutamate Transporters, and mGluR 2/3 Expression in P Rats Exposed to Ethanol

  • Yusuf S. Althobaiti
  • Fahad S. Alshehri
  • Alqassem Y. Hakami
  • Alaa M. Hammad
  • Youssef SariEmail author


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.


Methamphetamine Glutamatergic transporters Conditioned place preference mGluR2/3 Clavulanic acid 



The work was supported in part by Award Number R01AA019458 (Y.S.) from the National Institutes on Alcohol Abuse and Alcoholism and fund provided by The University of Toledo. The authors would like to thank Dr. F. Scott Hall for generously giving the access to use the ANY-maze video tracking system and Molly Hill for contribution in the experiments. The research work was completely performed at The University of Toledo, however, some of the writing and revision of this article were performed at Taif University by YSA.

Author Contributions

YSA participated in study design and conceptualization, drafted and revised the manuscript, and collected and analyzed the data. FSA participated in study design, collected the data, and helped with the editing of the manuscript. AYH collected the data and helped with the editing of the manuscript. AH performed the locomotor activity experiments and helped with editing the manuscript. YS conceptualized and designed the study, critically revised the manuscript for intellectual content, and approved the final version of the manuscript.

Compliance with Ethical Standards

Animal experimental procedures were approved by the Institutional Animal Care and Use Committee of The University of Toledo in accordance with the guidelines of the Institutional Animal Care and Use Committee of the National Institutes of Health and the Guide for the Care and Use of Laboratory Animals.

Conflict of Interest

The authors declare that they have no conflict of interest.


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Authors and Affiliations

  1. 1.College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental TherapeuticsUniversity of ToledoToledoUSA
  2. 2.College of Pharmacy, Department of Pharmacology and ToxicologyTaif UniversityTaifSaudi Arabia

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