Hakami Alqassem Y, Sari Youssef
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Neurosci Lett. 2017 Sep 14;657:140-145. doi: 10.1016/j.neulet.2017.08.013. Epub 2017 Aug 5.
Studies from our laboratory showed that upregulation of glutamate transporter 1 (GLT-1) and cystine-glutamate exchanger (xCT) expression with ceftriaxone, β-lactam antibiotic, in the brain was associated with attenuation of ethanol consumption. In this study, we tested clavulanic acid, which is another β-lactam compound with negligible antimicrobial activity, on ethanol consumption and expression of GLT-1, xCT and glutamate aspartate transporter (GLAST) in male alcohol-preferring (P) rats. Clavulanic acid has the central β-lactam pharmacophore that is critical for the upregulation of GLT-1 and xCT expression. We found that clavulanic acid, at 5mg/kg (i.p.) dose, significantly attenuated ethanol consumption and ethanol preference in P rats as compared to vehicle-treated group. This effect was associated with a significant increase in water intake in clavulanic acid treated group. Importantly, we found that clavulanic acid increased the expression of GLT-1 and xCT in nucleus accumbens. However, there was no effect of clavulanic acid on GLAST expression in the nucleus accumbens. Clavulanic acid treatment did not upregulate the expression of GLT-1, xCT and GLAST in prefrontal cortex. These findings revealed that clavulanic acid at 20-40 fold lower dose than ceftriaxone can attenuate ethanol consumption, in part through upregulation of GLT-1 and xCT expression in the nucleus accumbens. Thus, we suggest that clavulanic acid might be used as an alternative option to ceftriaxone to attenuate ethanol drinking behavior.
我们实验室的研究表明，在大脑中使用头孢曲松（一种β-内酰胺抗生素）上调谷氨酸转运体1（GLT-1）和胱氨酸-谷氨酸交换体（xCT）的表达与乙醇消耗量的减少有关。在本研究中，我们测试了克拉维酸（另一种抗菌活性可忽略不计的β-内酰胺化合物）对雄性嗜酒（P）大鼠乙醇消耗以及GLT-1、xCT和谷氨酸-天冬氨酸转运体（GLAST）表达的影响。克拉维酸具有中央β-内酰胺药效基团，这对于GLT-1和xCT表达的上调至关重要。我们发现，与溶剂处理组相比，5mg/kg（腹腔注射）剂量的克拉维酸显著降低了P大鼠的乙醇消耗量和乙醇偏好性。这种作用与克拉维酸处理组饮水量的显著增加有关。重要的是，我们发现克拉维酸增加了伏隔核中GLT-1和xCT的表达。然而，克拉维酸对伏隔核中GLAST的表达没有影响。克拉维酸处理并未上调前额叶皮质中GLT-1、xCT和GLAST的表达。这些发现表明，剂量比头孢曲松低20至40倍的克拉维酸可以部分通过上调伏隔核中GLT-1和xCT的表达来减少乙醇消耗。因此，我们建议克拉维酸可能作为头孢曲松的替代选择来减少乙醇饮用行为。
