Youssef Sari1,*, Jamie E. Toalston2, P.S.S. Rao1, Richard L. Bell2,*
1University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, OH 43614, USA, 2Department of Psychiatry and Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Increased glutamatergic neurotransmission appears to mediate the reinforcing properties of drugs of abuse, including ethanol (EtOH). Studies from our lab revealed that i.p. injections of ceftriaxone (CEF), a β-lactam antibiotic, reduced EtOH intake and increased glutamate transporter 1 (GLT-1, human homolog excitatory amino acid transporter 2, EAAT2) 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) and 10% SUC [SUC], (b) 5% SUC + 0.07 mg/ml NIC and 10% SUC + 0.14 mg/ml NIC [NIC-SUC], 15% EtOH and 30% EtOH [EtOH] and (d) 15% EtOH + 0.07 mg/ml NIC and 30% EtOH + 0.14 mg/ml NIC [NIC-EtOH]. After achieving stable intakes (4 weeks), the rats were administered 7 concurrent, daily i.p. injections of either saline or 100 mg/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.
Key words: Addiction; Alcohol; Ceftriaxone; Drinking; EAAT2; Polysubstance