Ceftriaxone, a beta-lactam antibiotic, attenuates relapse-like ethanol-drinking behavior in alcohol-preferring rats

Qrunfleh, Abeer Mostafa; Alazizi, Adnan; Sari, Youssef

doi:10.1177/0269881113482529

Cited by 70 publications

(65 citation statements)

References 63 publications

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“…A recent study from our laboratory demonstrated that CEF treatment attenuated relapse-like ethanol drinking in P rats and upregulated GLT-1 levels in the PFC and the NAc core (Qrunfleh et al 2013). In this study, we tested the effect of CEF on xCT in both continuous and relapse-like ethanol-drinking paradigms.…”

Section: Discussionmentioning

confidence: 99%

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Effects of ceftriaxone on ethanol intake: a possible role for xCT and GLT-1 isoforms modulation of glutamate levels in P rats

2014

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Rationale Evidence suggests that glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger transporter (xCT) are critical in maintaining glutamate homeostasis. We have recently demonstrated that ceftriaxone treatment induced up-regulation of GLT1 levels and attenuated ethanol intake; however, less is known about the involvement of xCT on ethanol intake. In this study, we investigated the effects of ceftriaxone on the levels of xCT in both continuous and relapse-like ethanol drinking, as well as GLT-1 isoforms, and glutamate aspartate transporter (GLAST) in relapse-like ethanol intake. Methods P rats received free choice of 15 and 30 % ethanol and water for 5 weeks and then deprived of ethanol for 2 weeks. Rats were treated with ceftriaxone (100 mg/kg, i.p.) or saline during the last 5 days of the 2-week deprivation period. After deprivation period, P rats were re-exposed to free choice of 15 and 30 % ethanol and water for nine consecutive days. A second group of P rats was given continuous ethanol access for 5 weeks, then ceftriaxone (100 mg/kg, i.p.) or saline throughout the week 6. Results Ceftriaxone significantly attenuated relapse-like ethanol intake. Importantly, this effect of ceftriaxone was associated in part with upregulation of the levels of GLT-1a and GLT-1b isoforms and xCT in the prefrontal cortex (PFC) and the nucleus accumbens (NAc). There were no significant differences in GLAST expression among all groups. We also found that ceftriaxone treatment increased xCT levels in both PFC and NAc in continuous ethanol intake. Conclusion These findings suggest that xCT and GLT-1 isoforms might be target proteins for the treatment of alcohol dependence.

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Section: Discussionmentioning

confidence: 99%

“…We have recently reported that ceftriaxone (CEF), a β-lactam antibiotic, attenuated relapse-like ethanol drinking and upregulated GLT-1 levels in the PFC and NAc in male alcohol-preferring (P) rats (Qrunfleh et al 2013; Sari et al 2011, 2013a, 2013b). …”

Section: Introductionmentioning

confidence: 99%

Effects of ceftriaxone on ethanol intake: a possible role for xCT and GLT-1 isoforms modulation of glutamate levels in P rats

2014

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“…Ceftriaxone treatment has proven to be effective in several drug abuse animal models (Abulseoud et al 2012; Alajaji et al 2013; Rasmussen et al 2011; Sari et al 2013a; Sari et al 2011; Sondheimer and Knackstedt 2011). Furthermore, ceftriaxone treatment has shown promising results in drug reinstatement studies as well (Knackstedt et al 2010; Qrunfleh et al 2013). …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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“…Up regulation of these specific glutamate transporters may decrease extracellular glutamate content. Interestingly, when administered to animal models of motor neuron degeneration, there was a delayed loss of neurons and muscle cells as well as a reduction of hypercellular gliosis, [34] which was associated with decreased extracellular glutamate levels [31,35]. The pathway involved in the activation of the promoter region of the GLT1 gene is unknown.…”

Section: Discussionmentioning

confidence: 99%

Ethane-β-Sultam Modifies the Activation of the Innate Immune System Induced by Intermittent Ethanol Administration in Female Adolescent Rats

Stefanini

et al. 2014

J Alcohol Drug Depend

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Intermittent ethanol abuse or 'binge drinking' during adolescence induces neuronal damage, which may be associated with cognitive dysfunction. To investigate the neurochemical processes involved, rats were administered either 1 g/kg or 2 g/kg ethanol in a 'binge drinking' regime. After only 3 weeks, significant activation of phagocytic cells in the peripheral (alveolar macrophages) and the hippocampal brain region (microglia cells) was present, as exemplified by increases in the release of pro-inflammatory cytokines in the macrophages and of iNOS in the microglia. This was associated with neuronal loss in the hippocampus CA1 region. Daily supplementation with a taurine prodrug, ethane-β-sultam, 0.028 g/kg, during the intermittent ethanol loading regime, supressed the release of the pro-inflammatory cytokines and of reactive nitrogen species, as well as neuronal loss, particularly in the rats administered the lower dose of ethanol, 1 g/kg. Plasma, macrophage and hippocampal taurine levels increased marginally after ethane-β-sultam supplementation. The 'binge drinking' ethanol rats administered 1 g/kg ethanol showed increased latencies to those of the control rats in their acquisition of spacial navigation in the Morris Water Maze, which was normalised to that of the controls values after ethane-β-sultam administration.Such results confirm that the administration of ethane-β-sultam to binge drinking rats reduces neuroinflammation in both the periphery and the brain, suppresses neuronal loss, and improved working memory of rats in a water maze study.

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Ceftriaxone, a beta-lactam antibiotic, attenuates relapse-like ethanol-drinking behavior in alcohol-preferring rats

Cited by 70 publications

References 63 publications

Effects of ceftriaxone on ethanol intake: a possible role for xCT and GLT-1 isoforms modulation of glutamate levels in P rats

Effects of ceftriaxone on ethanol intake: a possible role for xCT and GLT-1 isoforms modulation of glutamate levels in P rats

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

Ethane-β-Sultam Modifies the Activation of the Innate Immune System Induced by Intermittent Ethanol Administration in Female Adolescent Rats

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