Chronic ethanol-drinking or ethanol exposure significantly reduces glutamate uptake in the brain through downregulation of glutamate transporter, or antiporter, expression153–156 and reductions in glutamate transporter expression have been confirmed in postmortem evaluation of brains from alcoholics.128 Recent studies have examined the effects of modulating GLT-1, glial EAAT2, and the cystine–glutamate antiporter (xCT) on ethanol intake. Ceftriaxone, a beta-lactam antibiotic, increases glutamate reuptake by upregulating GLT1 expression.157 Given the general hyperglutamatergic state in alcohol/drug dependence, it is not surprising that this compound also decreases ethanol consumption, ethanol dependence (ED)-associated withdrawal signs, and withdrawal-associated escalation of ethanol intake in P rats.158–162 These authors reported a consistent upregulation of GLT1 expression in the Acb and mPFC, which was negatively associated with the observed reductions in ethanol consumption. Moreover, these authors have shown that ceftriaxone, or its analogs, significantly reduces ethanol intake and reverses chronic ethanol-induced downregulation of GLT1 expression in the mPFC, Acb, Amyg, and hippocampus, as well as reversing downregulation of xCT in some brain regions.153,163–166
