Modulatory effects of GLT-1 enhancer, MC-100093, on glutamate uptake and associated signaling pathways in female and male alcohol preferring rats exposed to ethanol.
Ahmed Alotaibi, Khokon Kanti Bhowmik, Woonyen Wong, Adil Shareef Mohammed, Magid Abou-Gharbia, Wayne Childers, Youssef Sari
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引用次数: 0
Abstract
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 homeostasis. Additionally, we focused on whether the effects of MC-100093 on GLT-1 are mediated through the mTOR, Akt, and NFkB signaling pathways.
Methods: Male and female alcohol-preferring (P) rats are grouped into four groups. Other than control groups all the three groups had free access to ethanol (15% and 30% v/v), and water for five weeks. On Week 6, rats received i.p. MC-100093 at a dosage of 100 mg/kg or 150 mg/kg, or saline, for five days. The Na+ dependent and Na+ independent glutamate uptake is measured by radioactive glutamate uptake assay. The expressions of GLT-1, XCT, mTOR, Akt, IkBa and NFkB are determined by Western Blot analysis.
Results: MC-100093 treatment resulted in 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, NFkB, 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.
期刊介绍：
The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
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