title: Effects of ceftriaxone on ethanol intake: a possible role for xCT and GLT-1 isoforms modulation of glutamate levels in P rats.
abstract: BACKGROUND
  Evidence suggests that glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger transporter (xCT) are critical in maintaining glutamate homeostasis. We have recently demonstrated that ceftriaxone treatment induced upregulation of GLT1 levels and attenuated ethanol intake; however, less is known about the involvement of xCT on ethanol intake. In this study, we investigated the effects of ceftriaxone on the levels of xCT in both continuous and relapse-like ethanol drinking, as well as GLT-1 isoforms, and glutamate aspartate transporter (GLAST) in relapse-like ethanol intake.
  
  
  METHODS
  P rats received free choice of 15 and 30 % ethanol and water for 5 weeks and then deprived of ethanol for 2 weeks. Rats were treated with ceftriaxone (100 mg/kg, i.p.) or saline during the last 5 days of the 2-week deprivation period. After deprivation period, P rats were re-exposed to free choice of 15 and 30 % ethanol and water for nine consecutive days. A second group of P rats was given continuous ethanol access for 5 weeks, then ceftriaxone (100 mg/kg, i.p.) or saline throughout the week 6.
  
  
  RESULTS
  Ceftriaxone significantly attenuated relapse-like ethanol intake. Importantly, this effect of ceftriaxone was associated in part with upregulation of the levels of GLT-1a and GLT-1b isoforms and xCT in the prefrontal cortex (PFC) and the nucleus accumbens (NAc). There were no significant differences in GLAST expression among all groups. We also found that ceftriaxone treatment increased xCT levels in both PFC and NAc in continuous ethanol intake.
  
  
  CONCLUSIONS
  These findings suggest that xCT and GLT-1 isoforms might be target proteins for the treatment of alcohol dependence.
authors.affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Alhaddad
authors.forename: Sujan C
authors.initials: SC
authors.lastname: Das
authors.forename: Youssef
authors.initials: Y
authors.lastname: Sari
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy / Q000378:metabolism*; D000437:Alcoholism / Q000188:drug therapy / Q000378:metabolism; D026922:Amino Acid Transport Systems, Acidic / Q000378:metabolism*; D000818:Animals; D002443:Ceftriaxone / Q000494:pharmacology* / Q000627:therapeutic use; D000431:Ethanol / Q000008:administration & dosage*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects; D027182:Amino Acid Transport System y+
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D002443:Ceftriaxone; D000431:Ethanol; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D020033:Protein Isoforms; C493392:Slc1a3 protein, rat; C000723960:Slc7a11 protein, rat; D027182:Amino Acid Transport System y+