Attenuation of ethanol withdrawal by ceftriaxone-induced upregulation of glutamate transporter EAAT2

Osama A. Abulseoud, Ulas M. Camsari, Christina L. Ruby, Aimen Kasasbeh, Sun Choi, Doo Sup Choi

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Alcohol withdrawal syndrome (AWS) is a potentially fatal outcome of severe alcohol dependence that presents a significant challenge to treatment. Although AWS is thought to be driven by a hyperglutamatergic brain state, benzodiazepines, which target the GABAergic system, comprise the first line of treatment for AWS. Using a rat model of ethanol withdrawal, we tested whether ceftriaxone, a β-lactam antibiotic known to increase the expression and activity of glutamate uptake transporter EAAT2, reduces the occurrence or severity of ethanol withdrawal manifestations. After a 2-week period of habituation to ethanol in two-bottle choice, alcohol-preferring (P) and Wistar rats received ethanol (4.0 g/kg) every 6 h for 3-5 consecutive days via gavage. Rats were then deprived of ethanol for 48 h during which time they received ceftriaxone (50 or 100 mg/kg, IP) or saline twice a day starting 12 h after the last ethanol administration. Withdrawal manifestations were captured by continuous video recording and coded. The evolution of ethanol withdrawal was markedly different for P rats vs Wistar rats, with withdrawal manifestations occurring >12 h later in P rats than in Wistar rats. Ceftriaxone 100 mg/kg per injection twice per day (200 mg/kg/day) reduced or abolished all manifestations of ethanol withdrawal in both rat variants and prevented withdrawal-induced escalation of alcohol intake. Finally, ceftriaxone treatment was associated with lasting upregulation of ethanol withdrawal-induced downregulation of EAAT2 in the striatum. Our data support the role of ceftriaxone in alleviating alcohol withdrawal and open a novel pharmacologic avenue that requires clinical evaluation in patients with AWS.

Original languageEnglish (US)
Pages (from-to)1674-1684
Number of pages11
JournalNeuropsychopharmacology
Volume39
Issue number7
DOIs
StatePublished - Jun 2014

Keywords

  • Animal models
  • alcohol-preferring rats
  • ceftriaxone
  • ethanol withdrawal
  • glutamate
  • glutamate transporter

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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