title: Effects of ceftriaxone on chronic ethanol consumption: a potential role for xCT and GLT1 modulation of glutamate levels in male P rats.
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.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, University of Toledo, 3000 Arlington Avenue, HEB282G, Toledo, OH, 43614, USA.
authors.forename: P S S
authors.initials: PS
authors.lastname: Rao
authors.forename: Youssef
authors.initials: Y
authors.lastname: Sari
mesh_terms: D000437:Alcoholism / Q000188:drug therapy / Q000378:metabolism*; D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002443:Ceftriaxone / Q000494:pharmacology* / Q000627:therapeutic use; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051381:Rats; D015854:Up-Regulation; D027182:Amino Acid Transport System y+
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D002443:Ceftriaxone; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; C493395:Slc1a2 protein, rat; C000723960:Slc7a11 protein, rat; D027182:Amino Acid Transport System y+