Effects of Ceftriaxone on Chronic Ethanol Consumption: a Potential Role for xCT and GLT1 Modulation of Glutamate Levels in Male P Rats

Rao, P.S.S.; Sari, Youssef

doi:10.1007/s12031-014-0251-5

Cited by 46 publications

(45 citation statements)

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“…It remains to be examined if the change in extracellular glutamate after ethanol exposure is mediated primarily by the downregulation of GLT-1 protein or the impaired transport function of GLT-1. Regardless, CEF treatment normalized GLT-1 protein levels in NAc and is consistent with earlier reports showing GLT-1 upregulation in NAc by CEF (Rothstein et al, 2005, Sari et al, 2010, Sari et al, 2011, Qrunfleh et al, 2013, Sari et al, 2013a, Sari et al, 2013b, Abulseoud et al, 2014, Rao and Sari, 2014). …”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, CEF is known to have neuroprotective effects (Mimura et al, 2011) and attenuated cocaine-seeking (Sari et al, 2009, Knackstedt et al, 2010, Sondheimer and Knackstedt, 2011), cannabinoid tolerance (Gunduz et al, 2011), amphetamine-induced hyperactivity and behavioral sensitization (Rasmussen et al, 2011a), and morphine-evoked hyperthermia (Rawls et al, 2007). CEF has also been reported to attenuate both chronic and relapse-like ethanol drinking (Sari et al, 2011, Qrunfleh et al, 2013, Sari et al, 2013a, Sari et al, 2013b, Alhaddad et al, 2014, Rao and Sari, 2014), and ethanol-withdrawal manifestations (Abulseoud et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

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Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats

et al. 2015

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Alteration of glutamatergic-neurotransmission is a hallmark of alcohol abuse. We have previously reported that chronic ethanol-drinking downregulated glutamate transporter 1 (GLT-1) in nucleus accumbens (NAc) in male P rats in a manner that was reversed by ceftriaxone treatment. However, the effect of ceftriaxone on extracellular glutamate concentrations in NAc after chronic ethanol-drinking has not yet been studied. In the present study, male P rats were treated with ceftriaxone (100 mg/kg/day, i.p.) for five consecutive days following five-weeks of free choice ethanol (15% and 30%) drinking. In vivo microdialysis was performed to measure the extracellular glutamate concentrations in NAc and the effect of blockade of GLT-1 with dihydrokainic acid (DHK) on extracellular glutamate in NAc of ceftriaxone-treated rats was determined. Ceftriaxone treatment attenuated ethanol intake as well as ethanol preference. Extracellular glutamate was significantly higher in NAc after five-weeks of ethanol drinking in saline-treated compared to water control rats. Ceftriaxone treatment blocked the increase extracellular glutamate produced by ethanol intake. Blockade of GLT-1 by DHK reversed the effects of ceftriaxone on glutamate and implicated the role of GLT-1 in the normalization of extracellular glutamate by ceftriaxone. In addition, GLT-1 protein was decreased in ethanol exposed animals and ceftriaxone treatment reversed this deficit. Ceftriaxone treatment also increased glutamine synthetase activity in NAc but not in PFC as compared to ethanol drinking saline-treated rats. Our present study demonstrates that ceftriaxone treatment prevents ethanol drinking in part through normalization of extracellular glutamate concentrations in NAc of male P rats via GLT-1.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats

et al. 2015

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“…Importantly, we have recently reported that chronic ethanol consumption was associated with significant downregulation of xCT levels in the NAc and PFC in P rats (Alhaddad et al 2014a). Ceftriaxone is known to upregulate xCT expressions and was found effective in abolishing drug-seeking behavior (Knackstedt et al 2010; Lewerenz et al 2009; Rao and Sari 2014a; Trantham-Davidson et al 2012). Given the possible role of xCT in the development of addiction, we have revealed in this study the ability of ceftriaxone to upregulate xCT expressions in the NAc and PFC of ethanol-dependent P rats compared to saline-treated animals.…”

Section: Discussionmentioning

confidence: 99%

“…Ceftriaxone, a β-lactam antibiotic, is a known modulator of the major glutamate transporters, glutamate transporter 1 (GLT1) and cystine/glutamate antiporter, xCT (system x c − ) (Knackstedt et al 2010; Lewerenz et al 2009; Rao and Sari 2014a; Rothstein et al 2005). 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).…”

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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“…[27]]. Several studies from our laboratory reported that the increases in xCT and GLT-1 expressions are linked to the attenuation of ethanol consumption in male P rats [14, 17, 18]. In addition, chronic consumption of ethanol can lead to downregulation of xCT expression in the NAc and PFC [13].…”

Section: Discussionmentioning

confidence: 99%

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

Alasmari

Abuhamdah

Sari

2015

Neuroscience Letters

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Evidence demonstrated that glial cells, mainly astrocytes, regulate glutamate uptake, which is regulated by several glutamate transporters. Among these glutamate transporters, glutamate transporter 1 (GLT-1; its human homolog is excitatory amino acid transporter-2) is responsible for the majority of glutamate uptake by glial cells. Cystine-glutamate antiporter (xCT) is another glial protein critical in regulating glutamate transmission. Several studies from our laboratory demonstrated that attenuation of ethanol intkae was associated in part with upregulation of xCT and GLT suggesting the important role of these transporters in the treatment of ethanol dependence. We found recently that β-lactam antibiotic, ampicillin, upregulated GLT-1 expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) and consequently reduced ethanol intake in alcohol-preferring (P) rats. In this study, we investigated the effects of ampicillin on the expressions of xCT and GLT-1 isoforms (GLT-1a and GLT-1b) as well as on GLAST expression. We found that ampicillin reduced ethanol intake as compared to the saline (control)-treated group. In addition, we found that ampicillin induced upregulation of xCT, GLT-1a, and GLT-1b expressions in both the PFC and NAc, but had no effect on GLAST expression. Our findings provide significant role of ampicillin on upregulating xCT and GLT-1 isoforms expressions, might be suggested as possible tragets for the attenuation of ethanol consumption.

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Effects of Ceftriaxone on Chronic Ethanol Consumption: a Potential Role for xCT and GLT1 Modulation of Glutamate Levels in Male P Rats

Cited by 46 publications

References 53 publications

Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats

Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats

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

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

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