Attenuation of ethanol withdrawal by ceftriaxone-induced upregulation of glutamate transporter EAAT2.
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.
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Osama A
OA
Abulseoud
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Ulas M
UM
Camsari
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
Christina L
CL
Ruby
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Aimen
A
Kasasbeh
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
Sun
S
Choi
1] Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
Doo-Sup
DS
Choi
D000428:Alcohol Drinking / Q000188:drug therapy; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002443:Ceftriaxone / Q000627:therapeutic use*; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004831:Epilepsies, Myoclonic / Q000209:etiology; D000431:Ethanol / Q000009:adverse effects*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D002492:Central Nervous System Depressants; D027342:Excitatory Amino Acid Transporter 2; C493395:Slc1a2 protein, rat; D000431:Ethanol; D002443:Ceftriaxone