Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2
Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2
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DOI：
10.1038/npp.2014.14
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发表时间：
2014-06-01
影响因子：
7.6
通讯作者：
Choi, Doo-Sup
中科院分区：
文献类型：
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作者：
Abulseoud, Osama A.;Camsari, Ulas M.;Choi, Doo-Sup
酒精戒断综合征 (AWS) 是严重酒精依赖的一种潜在致命后果，对治疗提出了重大挑战。尽管 AWS 被认为是由高谷氨酸能大脑状态驱动的，但针对 GABA 能系统的苯二氮卓类药物构成了 AWS 的一线治疗方法。使用乙醇戒断大鼠模型，我们测试了头孢曲松（一种已知可增加谷氨酸摄取转运蛋白 EAAT2 的表达和活性的 β-内酰胺抗生素）是否可以减少乙醇戒断症状的发生或严重程度。经过两周的两瓶选择习惯后，偏好酒精的 (P) 和 Wistar 大鼠每 6 小时接受一次乙醇 (4.0 g/kg)，连续 3-5 天通过灌胃法。然后，大鼠被剥夺乙醇 48 小时，在此期间，从最后一次乙醇给药后 12 小时开始，每天两次接受头孢曲松（50 或 100 mg/kg，IF）或盐水。通过连续视频记录捕获戒断表现并进行编码。 P 大鼠与 Wistar 大鼠的乙醇戒断进展明显不同，P 大鼠比 Wistar 大鼠晚 12 小时以上才出现戒断表现。每次注射头孢曲松 100 mg/kg，每天两次（200 mg/kg/天）可减少或消除两种大鼠变体中乙醇戒断的所有表现，并防止戒断引起的酒精摄入量增加。最后，头孢曲松治疗与纹状体中乙醇戒断诱导的 EAAT2 下调的持久上调相关。我们的数据支持头孢曲松在缓解酒精戒断中的作用，并开辟了一条需要对 AWS 患者进行临床评估的新药理学途径。
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 beta-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, IF) 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 >12 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.