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Effects of Ceftriaxone on Chronic Ethanol Consumption: a Potential Role for xCT and GLT1 Modulation of Glutamate Levels in Male P Rats

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Abstract

Alterations in glutamatergic neurotransmission have been suggested to affect many aspects of neuroplasticity associated with alcohol/drug addiction. We have previously shown that ceftriaxone, a β-lactam antibiotic known to upregulate glutamate transporter 1 (GLT1), reduced ethanol intake after 5 weeks of free choice ethanol drinking paradigm in male alcohol-preferring (P) rats. Evidence suggests that differential effects involving alterations of glutamatergic neurotransmission occur after long-term ethanol consumption. In this study, we tested whether the efficacy of administration of ceftriaxone persists after 14 weeks of free access to 15 and 30 % ethanol in male P rats. After 14 weeks of ethanol consumption, male P rats were administered ceftriaxone (100 mg/kg, intraperitoneal (i.p.)) or saline vehicle for 5 days. We found that ceftriaxone treatment resulted in a significant reduction in ethanol intake starting from day 2 (48 h after the first i.p. injections of ceftriaxone) through day 14, 10 days after final injection. Western blot analysis of brain samples from animals euthanized 24 h after treatment with the last dose of ceftriaxone revealed a significant upregulation of cystine/glutamate exchanger (xCT) and GLT1 levels in prefrontal cortex, nucleus accumbens, and amygdala as compared to saline vehicle-treated group. These findings demonstrated the effectiveness of ceftriaxone in attenuating ethanol intake in a chronic consumption paradigm. These might be due in part through the upregulation of both xCT and GLT1 levels in brain reward regions. Thus, the drug has a potential therapeutic action for the treatment of alcohol dependence.

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Acknowledgments

This work was supported by award number R01AA019458 (Y.S.) from the National Institutes on Alcohol Abuse and Alcoholism. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism or the National Institutes of Health.

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The authors declare no conflict of interest.

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  1. College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, University of Toledo, 3000 Arlington Avenue, HEB282G, Toledo, OH, 43614, USA

    P. S. S. Rao & Youssef Sari

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Correspondence to Youssef Sari.

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Rao, P.S.S., Sari, Y. Effects of Ceftriaxone on Chronic Ethanol Consumption: a Potential Role for xCT and GLT1 Modulation of Glutamate Levels in Male P Rats. J Mol Neurosci 54, 71–77 (2014). https://doi.org/10.1007/s12031-014-0251-5

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