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

Abstract

Rationale 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. Objectives We focus in this study to determine the effects of ceftriaxone, β-lactam antibiotic, on glial proteins such as GLT1 isoforms, xCT, 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 two-day versus five-day daily dosing of ceftriaxone. Results Ceftriaxone treatment (100 mg/kg), two-day and five day, 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 NAc and PFC of five-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 (two-day and five-day) demonstrated enhanced phosphorylation of Akt and nuclear translocation of NFκB in the NAc and PFC compared to control animals. Conclusions These findings demonstrate that ceftriaxone treatment induced upregulation of GLT1, GLT1 isoforms, and xCT in association with activation of Akt-NFκB signaling pathway.

Effects of ampicillin on cystine/glutamate antiporter and glutamate transporter 1 isoforms as well as ethanol drinking in male P rats

“…We did not observe an upregualtory effect on GLAST expression with ampicillin treatment. This effect is in accordance with a recent finding demonstrating that ceftriaxone treatment did not induce an upregulatory effect on GLAST expression [13, 15]. …”

“…It has been reported that ceftriaxone-induced attenuation of ethanol intake and relapse-like ethanol drinking in male P rats is associated in part with upregulation of GLT-1 and its isoforms (GLT-1a and GLT-1b) in the NAc and PFC [13, 15, 17, 19]. The upregulatory effects on GLT-1 could be associated with a decrease in extracellular glutamate concentrations leading to the reduction in ethanol intake.…”

Effects of cefazolin and cefoperazone on glutamate transporter 1 isoforms and cystine/glutamate exchanger as well as alcohol drinking behavior in male alcohol-preferring rats

“…For example, in motor cortex of patients with amyotrophic lateral sclerosis the expression of GLT-1a is downregulated while GLT-1b expression is upregulated (Maragakis et al, 2004). Previous studies from our laboratory have demonstrated that ceftriaxone-induced GLT-1a and GLT-1b expression in NAc and PFC, and this effect was found associated with a significant decrease in continuous ethanol intake and relapse-like ethanol drinking in male P rats (Alhaddad et al, 2014a; Rao et al, 2015b). In order to investigate differential effects on GLT-1a and GLT-1b expression, in this study, we tested the effects of both cefazolin and cefoperazone on GLT-1a and GLT-1b expression in P rats exposed to free choice ethanol (15% and 30%).…”

“…Therefore, GLT-1 upregulators are rationalized as potential treatment option for treating alcohol addiction. Following the discovery by Rothstein et al reported β-lactam antibiotics as potent GLT-1 upregulators (Rothstein et al, 2005), we have shown that ceftriaxone, a β-lactam antibiotic, reduced ethanol intake and relapse to ethanol intake presumably by increasing the expression of GLT-1 in the mesocorticolimbic areas of the brain including NAc and PFC (Alhaddad et al, 2014a; Qrunfleh et al, 2013; Rao and Sari, 2014; Rao et al, 2015b). Similarly, other β-lactams, including cefazolin and cefoperazone at dose of 100 mg/kg/day for 5 consecutive days, were found to be effective in reducing ethanol intake in male P rats (Rao et al, 2015a).…”

Amoxicillin and amoxicillin/clavulanate reduce ethanol intake and increase GLT-1 expression as well as AKT phosphorylation in mesocorticolimbic regions

“…Also, recovery of ethanol intake following AMOX and AUG treatment was not assessed, thus it remains to be seen whether the observed effects of these drugs are long-term or if the ethanol intake is only reduced in the presence of the drugs. Finally, it would be important to study the effects of these drugs on sodium independent glutamate uptake since another β-lactam antibiotic, CEF, has also been shown to modulate the expression of the cysteine/glutamate exchanger (xCT) (Rao et al, 2015). …”