Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Ave, Toledo, OH, USA.
Department of Pharmacy, College of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130 Amman, 11733, Jordan.
Alcohol Alcohol. 2020 Apr 16;55(3):254-263. doi: 10.1093/alcalc/agaa010.
Glutamate has been considered as neurotransmitter that is critical in triggering relapse to drugs of abuse, including ethanol and cocaine. Extracellular glutamate concentrations are tightly regulated by several mechanisms, including reuptake through glutamate transporters. Glutamate transporter type 1 (GLT-1) is responsible for clearing the majority of extracellular glutamate. The astrocytic cystine/glutamate antiporter (xCT) regulates also glutamate homeostasis. In this study, we investigated the effects of cocaine exposure and ampicillin/sulbactam (AMP/SUL), a β-lactam antibiotic known to upregulate GLT-1 and xCT, on relapse-like ethanol intake and the expression of astrocytic glutamate transporters in mesocorticolimbic brain regions.
Male alcohol-preferring (P) rats had free access to ethanol for 5 weeks. On Week 6, rats were exposed to either cocaine (20 mg/kg, i.p.) or saline for 12 consecutive days. Ethanol bottles were then removed for 7 days; during the last 5 days, either AMP/SUL (100 or 200 mg/kg, i.p.) or saline was administered to the P rats. Ethanol bottles were reintroduced, and ethanol intake was measured for 4 days.
Cocaine exposure induced an alcohol deprivation effect (ADE), which was associated in part by a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc) core. AMP/SUL (100 mg/kg, i.p.) attenuated the ADE, while AMP/SUL (200 mg/kg, i.p.) reduced ethanol intake during 4 days of ethanol re-exposure and upregulated GLT-1 and xCT expression in the NAc core, NAc shell and dorsomedial prefrontal cortex (dmPFC).
This study suggests that these astrocytic glutamate transporters might be considered as potential targets for the treatment of polysubstance abuse.
谷氨酸被认为是触发包括乙醇和可卡因在内的滥用药物复吸的关键神经递质。细胞外谷氨酸浓度受多种机制的严格调节，包括通过谷氨酸转运体进行再摄取。谷氨酸转运体 1（GLT-1）负责清除大部分细胞外谷氨酸。星形胶质细胞胱氨酸/谷氨酸反向转运体（xCT）也调节谷氨酸稳态。在这项研究中，我们研究了可卡因暴露和氨苄西林/舒巴坦（AMP/SUL）对复发性乙醇摄入和中边缘皮质脑区星形胶质细胞谷氨酸转运体表达的影响，AMP/SUL 是一种已知能上调 GLT-1 和 xCT 的β-内酰胺抗生素。
雄性酒精偏好（P）大鼠自由饮用乙醇 5 周。第 6 周，大鼠连续 12 天接受可卡因（20mg/kg，ip）或生理盐水处理。然后取出乙醇瓶 7 天；在最后 5 天，给 P 大鼠注射 AMP/SUL（100 或 200mg/kg，ip）或生理盐水。重新引入乙醇瓶，并测量 4 天的乙醇摄入量。
可卡因暴露诱导了酒精剥夺效应（ADE），部分原因是伏隔核（NAc）核心中 GLT-1 和 xCT 的表达下降。AMP/SUL（100mg/kg，ip）减弱了 ADE，而 AMP/SUL（200mg/kg，ip）减少了 4 天乙醇再暴露期间的乙醇摄入量，并上调了 NAc 核心、NAc 壳和背内侧前额叶皮质（dmPFC）中的 GLT-1 和 xCT 表达。
这项研究表明，这些星形胶质细胞谷氨酸转运体可能被视为治疗多种物质滥用的潜在靶点。
