Effects of ceftriaxone on GLT1 isoforms, xCT and associated signaling pathways in P rats exposed to ethanol.

Abstract

Several studies have demonstrated a correlation between extracellular glutamate concentration in the mesolimbic reward pathway and alcohol craving. Extracellular glutamate concentration is regulated by several glutamate transporters. Glial glutamate transporter 1 (GLT1) is one of them that regulates the majority of extracellular glutamate concentration. In addition, cystine/glutamate antiporter (xCT) is another transporter that regulates extracellular glutamate. We focus in this study to determine the effects of ceftriaxone, β-lactam antibiotic, on glial proteins such as GLT1 isoforms, xCT, glutamate aspartate transporter (GLAST), and several associated signaling pathways as well as ethanol intake in P rats. Additionally, to examine the onset of signaling pathways associated with GLT1 upregulation following ceftriaxone treatment, we tested 2- versus 5-day daily dosing of ceftriaxone. Ceftriaxone treatment (100mg/kg), 2 and 5days, resulted in about five fold reduction in ethanol intake by P rats. The reduction in ethanol intake was associated with significantly enhanced expression of GLT1, GLT1a, GLT1b, and xCT in the nucleus accumbens (NAc) and prefrontal cortex (PFC) of 5-day ceftriaxone-treated P rats. Two-day-treated P rats showed marked changes in expression of these glutamate transporters in the PFC but not in the NAc. Importantly, ceftriaxone-treated P rats (2 and 5days) demonstrated enhanced phosphorylation of Akt and nuclear translocation of nuclear factor kappaB (NFκB) in the NAc and PFC compared to control animals. These findings demonstrate that ceftriaxone treatment induced upregulation of GLT1, GLT1 isoforms, and xCT in association with activation of the Akt-NFκB signaling pathway.