Effects of MC-100093, GLT-1 enhancer, in mesolimbic brain regions of C57BL/6 mouse exposed to hydrocodone high-dose challenge using comprehensive laboratory monitoring system

Chronic exposure and overdose of opioid cause neurotoxicity through alterations of several neurotransmitters, including glutamate. Upregulating glutamate transporter 1 (GLT-1) has been shown to attenuate the behavioral and neurochemical effects of chronic drug abuse. This study investigated the effects of GLT-1 enhancers—MC-100093 and ceftriaxone—on locomotor activity, respiratory exchange, and glutamate transporters (GLT-1, cystine/glutamate transporter, xCT), trophic factor (BDNF), and neuroinflammatory biomarkers (TNF-α and HMGB1) in nucleus accumbens (NAc) and amygdala (AMY) of C57BL/6 mice exposed to escalated doses of hydrocodone. Male C57BL/6 mice were injected with hydrocodone (20mg/kg, i.p.) every other day for 13 days and then received a higher dose of hydrocodone (40mg /kg, i.p.) on day 15. Control group received i.p. injection of saline every other day, and mice in treatment groups received MC-100093 (50mg/kg, i.p.) or ceftriaxone (200mg/kg, i.p.) during the last five days. This study used comprehensive laboratory animal monitoring system (CLAMS) to measure mice's respiratory frequency, locomotor activity, oxygen consumption (VO₂), and carbon dioxide production (VCO₂). The high-dose hydrocodone challenge significantly increased VO₂ and VCO₂ while reducing the respiratory exchange ratio (RER). MC-100093 and ceftriaxone attenuated hydrocodone-induced increases in VO₂ and VCO₂; however, restoration of RER occurred exclusively in MC-100093-treated mice. Furthermore, high-dose of hydrocodone downregulated GLT-1, xCT and BDNF expression, while upregulating TNF- α and HMGB1 in both the NAc and AMY. Notably, treatment with either MC-100093 or ceftriaxone significantly mitigated these molecular alterations. These findings suggest that the novel β -lactam compound MC-100093 holds therapeutic potential in preventing or mitigating opioid-induced neurotoxicity and overdose effects.