Abulseoud Osama A, Camsari Ulas M, Ruby Christina L, Kasasbeh Aimen, Choi Sun, Choi Doo-Sup
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
Neuropsychopharmacology. 2014 Jun;39(7):1674-84. doi: 10.1038/npp.2014.14. Epub 2014 Jan 23.
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 β-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 >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.
酒精戒断综合征（AWS）是严重酒精依赖的一种潜在致命后果，对治疗构成重大挑战。尽管AWS被认为是由大脑谷氨酸能亢进状态驱动的，但针对γ-氨基丁酸能系统的苯二氮䓬类药物却是AWS的一线治疗药物。我们使用乙醇戒断大鼠模型，测试了已知能增加谷氨酸摄取转运体EAAT2表达和活性的β-内酰胺抗生素头孢曲松是否能减少乙醇戒断表现的发生或严重程度。在两瓶选择中对酒精偏好型（P）大鼠和Wistar大鼠进行为期2周的乙醇适应期后，连续3 - 5天，每6小时通过灌胃给予它们乙醇（4.0 g/kg）。然后让大鼠戒断乙醇48小时，在此期间，从最后一次给予乙醇12小时后开始，每天两次给予它们头孢曲松（50或100 mg/kg，腹腔注射）或生理盐水。通过连续视频记录捕捉戒断表现并进行编码。P大鼠和Wistar大鼠的乙醇戒断演变明显不同，P大鼠的戒断表现比Wistar大鼠晚出现12小时以上。每天两次注射100 mg/kg头孢曲松（200 mg/kg/天）可减少或消除两种大鼠模型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下调的持续上调有关。我们的数据支持头孢曲松在减轻酒精戒断方面的作用，并开辟了一条新的药理学途径，需要对AWS患者进行临床评估。
