Pharmacological actions of novel beta-lactam and non-beta lactam compounds on major astrocytic glutamate transporters in the brain and liver of male C57BL/6 mice exposed chronically to hydrocodone.

Chronic exposure to opioid reduced the expression of astrocytic glutamate transporter 1 (GLT-1) and cystine/glutamate antiporter (xCT) in the mesocorticolimbic brain region and ceftriaxone, a beta-lactam antibiotic, attenuated this effect. Importantly, a novel synthetic non-antibiotic beta-lactam, MC-100093, was found effective in attenuating fentanyl and morphine overdose-induced reduction in GLT-1 expression in the nucleus accumbens (NAc) as well as attenuated fentanyl-induced liver inflammation and disruption of liver metabolites. In the present study, two novel synthetic non-antibiotic beta-lactams, MC-100093 and MC-290401, and one novel synthetic non-beta-lactam bicyclic, MC-290013, were tested in a mouse model of chronic exposure to hydrocodone with focus on GLT-1 expression as well as the transcriptional regulation of GLT-1. This study reports that MC-100093, MC-290401, and MC-290013 treatment attenuated hydrocodone-induced downregulation of GLT-1 in the NAc. MC-100093, MC-290401, and MC-290013 treatments normalized GLT-1 and xCT expression in the NAc, and this effect was associated with upregulation of NFκB in the nuclear fraction and downregulation of the expression of mTOR and IKB-α in the cytoplasmic fraction as well as upregulation of pAkt expression in the NAc. Furthermore, histological and statistical analyses revealed that MC-100093, MC-290401, and MC-290013 treatments attenuated chronic hydrocodone-induced liver inflammation (TNF-α, IL-1β, and IL-6). Finally, these GLT-1 modulators attenuated hydrocodone-induced upregulation of hepatic xCT and GLT-1. These findings suggest that these novel synthetic GLT-1 modulators may be considered as potential agents to attenuate hydrocodone-induced alterations in glutamate transporters and associated target proteins in the brain and liver.