Ceftriaxone Treatment Affects the Levels of GLT1 and ENT1 As Well As Ethanol Intake in Alcohol-Preferring Rats

Sari, Youssef; Sreemantula, S.N.; Lee, Moonnoh R.; Choi, Doo Sup

doi:10.1007/s12031-013-0064-y

Cited by 85 publications

(93 citation statements)

References 30 publications

(53 reference statements)

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“…We used two doses of ceftriaxone; 100 and 200 mg/kg/day following the original study by Rothstein et al (2005), which showed that ceftriaxone 200 mg/kg/day administered to rats for 5 days was associated with a threefold increase in EAAT2 protein expression in the hippocampus and spinal cord. Along with others (Sari et al, 2011(Sari et al, , 2013Knackstedt et al, 2010;Lee et al, 2013), we (Abulseoud et al, 2012) have shown significant efficacy for ceftriaxone 200 mg/kg/day in upregulating glutamate transporter in different models of addiction.…”

Section: Ceftriaxone Administrationmentioning

confidence: 63%

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

Abulseoud

Camsari

Ruby

et al. 2014

Neuropsychopharmacol

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Alcohol withdrawal syndrome (AWS) is a potentially fatal outcome of severe alcohol dependence that presents a significant challenge to treatment. Although AWS is thought to be driven by a hyperglutamatergic brain state, benzodiazepines, which target the GABAergic system, comprise the first line of treatment for AWS. Using a rat model of ethanol withdrawal, we tested whether ceftriaxone, a b-lactam antibiotic known to increase the expression and activity of glutamate uptake transporter EAAT2, reduces the occurrence or severity of ethanol withdrawal manifestations. After a 2-week period of habituation to ethanol in two-bottle choice, alcohol-preferring (P) and Wistar rats received ethanol (4.0 g/kg) every 6 h for 3-5 consecutive days via gavage. Rats were then deprived of ethanol for 48 h during which time they received ceftriaxone (50 or 100 mg/kg, IP) or saline twice a day starting 12 h after the last ethanol administration. Withdrawal manifestations were captured by continuous video recording and coded. The evolution of ethanol withdrawal was markedly different for P rats vs Wistar rats, with withdrawal manifestations occurring 412 h later in P rats than in Wistar rats. Ceftriaxone 100 mg/ kg per injection twice per day (200 mg/kg/day) reduced or abolished all manifestations of ethanol withdrawal in both rat variants and prevented withdrawal-induced escalation of alcohol intake. Finally, ceftriaxone treatment was associated with lasting upregulation of ethanol withdrawal-induced downregulation of EAAT2 in the striatum. Our data support the role of ceftriaxone in alleviating alcohol withdrawal and open a novel pharmacologic avenue that requires clinical evaluation in patients with AWS.

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Section: Ceftriaxone Administrationmentioning

confidence: 63%

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

Abulseoud

Camsari

Ruby

et al. 2014

Neuropsychopharmacol

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“…We recently reported that rats exposed to free-choice ethanol for 5 weeks showed down-regulation of GLT1 levels in the NAc but not in the PFC (Sari and Sreemantula, 2012; Sari et al, 2013b). Furthermore, i.p.…”

Section: Discussionmentioning

confidence: 99%

Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats

Alhaddad

Kim

Aal-Aaboda

et al. 2014

Front. Behav. Neurosci.

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We have recently shown that upregulation of glutamate transporter 1 (GLT1) in the brain is associated in part with reduction in ethanol intake in alcohol-preferring (P) male rats. In this study, we investigated the effects of a synthetic compound, (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), known to activate GLT1 on ethanol consumption as well as GLT1 expression and certain signaling pathways in P rats. P rats were given 24-h concurrent access to 15 and 30% ethanol, water and food for 5 weeks. On week 6, P rats received MS-153 at a dose of 50 mg/kg (i.p.) or a vehicle (i.p.) for 5 consecutive days. We also tested the effect of MS-153 on daily sucrose (10%) intake. Our studies revealed a significant decrease in ethanol intake at the dose of 50 mg/kg MS-153 from Day 1 through 14. In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake. Importantly, we found that MS-153 upregulated the GLT1 level in the nucleus accumbens (NAc) but not in the prefrontal cortex (PFC). In accordance, we found upregulation of nuclear NFkB-65 level in NAc in MS-153-treated group, however, IkBα was downregulated in MS-153-treated group in NAc. We did not find any changes in NFkB-65 and IkBα levels in PFC. Interestingly, we revealed that p-Akt was downregulated in ethanol vehicle treated groups in the NAc; this downregulation was reversed by MS-153 treatment. We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups. These findings reveal MS-153 as a GLT1 modulator that may have potential as a therapeutic drug for the treatment of alcohol dependence.

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“…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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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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Ceftriaxone Treatment Affects the Levels of GLT1 and ENT1 As Well As Ethanol Intake in Alcohol-Preferring Rats

Cited by 85 publications

References 30 publications

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats

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

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