Modulatory effects of GLT-1 enhancer, MC-100093, on neuroinflammatory factors in mesocorticolimbic brain regions of female P rats exposed chronically to ethanol.

Chronic ethanol intake increases extracellular glutamate concentrations in important reward-related brain regions, including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), ultimately resulting in oxidative stress and inflammation. Recent studies from our laboratory demonstrated that MC-100093, a synthetic beta-lactam lacking antibacterial properties and functioning as a GLT-1 modulator, decreased ethanol consumption. This study examined the impact of the GLT-1 modulator, MC-100093, on chronic ethanol consumption and neuroinflammation in specific subregions of the NAc (core and shell) and mPFC (Prelimbic, PL; and Infralimbic, IL) in female alcohol preferring rats in a dose-dependent manner. MC-100093 treatment decreased ethanol consumption at both doses (100 and 150 mg/kg, i.p.) following a five-week drinking paradigm. MC-100093 attenuated ethanol-induced increase of the pro-inflammatory cytokines HMGβ-1 and TNF-α expression across all investigated mesocorticolimbic brain regions. Moreover, MC-100093 treatment attenuated the ethanol-induced increase of RAGE expression in these brain regions at both doses. MC-100093 treatment decreased ethanol consumption, and this behavioral outcome correlated with a reduction in pro-inflammatory markers, indicating that MC-100093 may serve as a potential agent for mitigating the effects of chronic ethanol exposure associated with inflammation.