2025/10/06 by Ahmed Alotaibi, Khokon Kanti Bhowmik, Woonyen Wong +4 · 1 voice
Neuroscience · Nursing · #Biochemical Analysis and Sensing Techniques #Neuroscience and Neuropharmacology Research #Neurotransmitter Receptor Influence on Behavior
paper · pdf · doi:10.1093/ijnp/pyaf075
openalex publication_date 2025/10/06 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
BACKGROUND: Ethanol consumption disrupts glutamate homeostasis in several brain regions. The uptake of extracellular glutamate is regulated in the majority by the astrocytic glutamate transporter 1 (GLT-1), and cystine-glutamate exchanger (xCT) contributes to this regulatory effect. Chronic ethanol consumption is well known to downregulate GLT-1 expression in several reward brain regions, including the nucleus accumbens (NAc). OBJECTIVES: Recently, we reported that a novel beta-lactam, MC-100093, attenuated ethanol consumption and normalized the expression of GLT-1 in the subregions of the NAc. Based on these findings, we aimed in this study to determine the dose-dependent effect of MC-100093 in attenuating ethanol consumption and whether this attenuating effect is associated with restoration of glutamate uptake. In addition, we focused on whether the effects of MC-100093 on GLT-1 are mediated through the mammalian target of rapamycin (mTOR), protein kinase B (Akt), and nuclear factor-kappa B (NF-κB) signaling pathways. METHODS: Male and female alcohol-preferring (P) rats are grouped into 4 groups. Other than control groups all the 3 groups had free access to ethanol (15% and 30% v/v), and water for 5 weeks. On week 6, rats received intraperitoneal injection (i.p.) of MC-100093 at a dosage of 100 or 150 mg/kg, or saline, for 5 days. The Na+ dependent and Na+ independent glutamate uptake is measured by radioactive glutamate uptake assay. The expression of GLT-1, xCT, mTOR, phospho-Akt (p-Akt), kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBa), and NF-κB are determined by Western blot analysis. RESULTS: MC-100093 treatment reduced ethanol drinking in male and female P rats. MC-100093 was associated with an increase in Na+-dependent and Na+-independent glutamate uptake. Furthermore, MC-100093 treatment attenuated ethanol-induced decrease in GLT-1, xCT, NF-κB, and p-Akt expression in the NAc. CONCLUSIONS: These findings demonstrate that MC-100093 attenuated ethanol consumption and regulated glutamate uptake through normalizing GLT-1 expression.