Modulatory effects of MC‑100093 on astrocytic glutamate transporters and attenuation of relapse-like ethanol drinking behavior in alcohol‑preferring rats

BACKGROUND: Relapse-like ethanol drinking behavior depends on changes in glutamate homeostasis in the mesocorticolimbic circuit. Extracellular glutamate regulation involves multiple transporters, mainly glutamate transporter 1 (GLT-1), which primarily removes the majority of extracellular glutamate; and cystine/glutamate antiporter (xCT) is co-localized with GLT-1 to be involved in this mechanism of maintaining glutamate homeostasis. AIMS: Recent studies showed that MC-100093 treatment (i.p.), a β-lactam non-antibiotic known to increase GLT-1 and xCT expression, reduced chronic ethanol consumption in male and female alcohol-preferring (P) rats. This study examined whether MC-100093 may reduce relapse-like ethanol drinking behavior. METHODS: P rats (both male and female) had access to 15% and 30% ethanol and water for 5 weeks and were treated with MC-100093 (100 mg/kg, i.p.) during the last 4 days of a 1-week deprivation period (week 6), continuing into 3 days of re-exposure (week 7). RESULTS: MC-100093-treated rats exhibited lower ethanol intake and preference during re-exposure compared to saline-treated groups, across sexes. Additionally, MC-100093 treatment showed a sex difference in ethanol intake and preference after re-exposure. Moreover, MC-100093 attenuated ethanol-induced downregulation of GLT-1 and xCT expression in the medial prefrontal cortex (Prelimbic, PL; and Infralimbic, IL) and nucleus accumbens (core and shell) regions. Importantly, MC-100093 did not affect rat body weights. CONCLUSIONS: These results report for the first time the efficacy of GLT-1 modulator, MC-100093, on attenuating relapse-like ethanol drinking behaviors.