title: Effects of ceftriaxone on ethanol, nicotine or sucrose intake by alcohol-preferring (P) rats and its association with GLT-1 expression.
abstract: Increased glutamatergic neurotransmission appears to mediate the reinforcing properties of drugs of abuse, including ethanol (EtOH). We have shown that administration of ceftriaxone (CEF), a β-lactam antibiotic, reduced EtOH intake and increased glutamate transporter 1 (GLT-1) expression in mesocorticolimbic regions of male and female alcohol-preferring (P) rats. In the present study, we tested whether CEF administration would reduce nicotine (NIC) and/or EtOH intake by adult female P rats. P rats were randomly assigned to 4 groups: (a) 5% sucrose (SUC) or 10% SUC [SUC], (b) 5% SUC+0.07mg/ml NIC and 10% SUC+0.14mg/ml NIC [NIC-SUC], 15% EtOH and 30% EtOH [EtOH] and (d) 15% EtOH+0.07mg/ml NIC and 30% EtOH+0.14mg/ml NIC [NIC-EtOH]. After achieving stable intakes (4weeks), the rats were administered 7 consecutive, daily i.p. injections of either saline or 200mg/kg CEF. The effects of CEF on intake were significant but differed across the reinforcers; such that ml/kg/day SUC was reduced by ∼30%, mg/kg/day NIC was reduced by ∼70% in the NIC-SUC group and ∼40% in the EtOH-NIC group, whereas g/kg/day EtOH was reduced by ∼40% in both the EtOH and EtOH-NIC group. The effects of CEF on GLT-1 expression were also studied. We found that CEF significantly increased GLT-1 expression in the prefrontal cortex and the nucleus accumbens of the NIC and NIC-EtOH rats as compared to NIC and NIC-EtOH saline-treated rats. These findings provide further support for GLT-1-associated mechanisms in EtOH and/or NIC abuse. The present results along with previous reports of CEF's efficacy in reducing cocaine self-administration in rats suggest that modulation of GLT-1 expression and/or activity is an important pharmacological target for treating polysubstance abuse and dependence.
authors.affiliation: University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, OH 43614, USA. Electronic address: youssef.sari@utoledo.edu.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Sari
authors.affiliation: Department of Psychiatry and Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Toalston
authors.affiliation: University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, OH 43614, USA.
authors.forename: P S S
authors.initials: PSS
authors.lastname: Rao
authors.affiliation: Department of Psychiatry and Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: ribell@iupui.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bell
mesh_terms: D000428:Alcohol Drinking; D000437:Alcoholism / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects*; D002443:Ceftriaxone / Q000008:administration & dosage*; D000431:Ethanol / Q000008:administration & dosage*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005260:Female; D009538:Nicotine / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage*; D014029:Tobacco Use Disorder / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D027342:Excitatory Amino Acid Transporter 2; C493395:Slc1a2 protein, rat; D000431:Ethanol; D013395:Sucrose; D009538:Nicotine; D002443:Ceftriaxone
keywords: EAAT2; addiction; alcohol; ceftriaxone; drinking; polysubstance