title: Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats.
abstract: Alteration of glutamatergic-neurotransmission is a hallmark of alcohol dependence. We have previously reported that chronic ethanol-drinking downregulated glutamate transporter 1 (GLT-1) in nucleus accumbens (NAc) in male P rats in a manner that was reversed by ceftriaxone treatment. However, the effect of ceftriaxone on extracellular glutamate concentrations in NAc after chronic ethanol-drinking has not yet been studied. In the present study, male P rats were treated with ceftriaxone (100 mg/kg/day, i.p.) for five consecutive days following five-weeks of free choice ethanol (15% and 30%) drinking. In vivo microdialysis was performed to measure the extracellular glutamate concentrations in NAc and the effect of blockade of GLT-1 with dihydrokainic acid (DHK) on extracellular glutamate in NAc of ceftriaxone-treated rats was determined. Ceftriaxone treatment attenuated ethanol intake as well as ethanol preference. Extracellular glutamate was significantly higher in NAc after five-weeks of ethanol drinking in saline-treated compared to water control rats. Ceftriaxone treatment blocked the increase extracellular glutamate produced by ethanol intake. Blockade of GLT-1 by DHK reversed the effects of ceftriaxone on glutamate and implicated the role of GLT-1 in the normalization of extracellular glutamate by ceftriaxone. In addition, GLT-1 protein was decreased in ethanol exposed animals and ceftriaxone treatment reversed this deficit. Ceftriaxone treatment also increased glutamine synthetase activity in NAc but not in PFC as compared to ethanol drinking saline-treated rats. Our present study demonstrates that ceftriaxone treatment prevents ethanol drinking in part through normalization of extracellular glutamate concentrations in NAc of male P rats via GLT-1.
authors.affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
authors.forename: Sujan C
authors.initials: SC
authors.lastname: Das
authors.affiliation: Department of Neurosciences, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, University of Toledo College of Medicine, Toledo, OH, USA.
authors.forename: Alexandar M
authors.initials: AM
authors.lastname: Hristov
authors.affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA. Electronic address: youssef.sari@utoledo.edu.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Sari
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000378:metabolism; D000437:Alcoholism / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002443:Ceftriaxone / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
chemical_list: D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D027342:Excitatory Amino Acid Transporter 2; C493395:Slc1a2 protein, rat; D000431:Ethanol; D018698:Glutamic Acid; C020889:dihydrokainic acid; D002443:Ceftriaxone; D005974:Glutamate-Ammonia Ligase; D007608:Kainic Acid
keywords: Alcohol dependence; Ceftriaxone; Dihydrokainic acid; GLT-1; No-net-flux microdialysis