Effects of MC-100093, GLT-1 enhancer, in mesocorticolimbic brain regions of C57BL/6 mouse exposed to hydrocodone overdose using comprehensive laboratory monitoring system
Y. Sari1, W. Wong1, W. Childers2, M. Abou-Gharbia2
1University of Toledo, Pharmacology and Experimental Therapeutics, Toledo, United States, 2Temple University, Pharmaceutical Sciences, Philadelphia, United States
Background: Chronic exposure and overdose of opioid cause neurotoxicity through alterations of several neurotransmitters, including glutamate. Targeting glutamate transporter 1 (GLT-1) may attenuate the effects of chronic exposure to drugs of abuse. Thus, the effects of novel GLT-1 enhancer, MC-100093, and β-lactam ceftriaxone, were evaluated in C57BL/6 mice exposed to hydrocodone overdose.
Aims & Objectives: This study focused on investigating the effects of MC-100093, and ceftriaxone on locomotor activity, respiratory exchange, and glutamatergic system (mGLUTR5, GLT-1 and cystine/glutamate transporter, xCT) as well as trophic (BDNF) and neuroinflammatory biomarkers (TNF-α and HMGB1) in the nucleus accumbens (NAc), amygdala (AMY), and dorsomedial prefrontal cortex (dmPFC) of C57BL/6 mice exposed to escalated doses of hydrocodone involving overdose.
Method: Male C57BL/6 mice were injected with hydrocodone (20 mg/kg, i.p.) every other day for 13 days, and then received a higher dose of hydrocodone (40 mg /kg, i.p.) on day 15. Control group received i.p. injection of saline every other day, and the mice in the treatment groups received MC-100093 (50 mg/kg, i.p.) or ceftriaxone (200 mg/kg, i.p.) during the last five days of the study. This study used comprehensive laboratory animal monitoring system (CLAMS) to measure mice's respiratory frequency, locomotor activity, oxygen consumption, and carbon dioxide production.
Results: Exposure to hydrocodone overdose increased oxygen consumption and carbon dioxide production, MC-100093 and ceftriaxone treatments attenuated these effects. Furthermore, hydrocodone overdose increased mGluR1 expression and decreased GLT-1 and xCT expression in the NAc, AMY, and dmPFC. Hydrocodone overdose upregulated TNF-α, and HMGB1, and decreased BDNF expression in the NAc, AMY and dmPFC. Importantly, MC-100093 and ceftriaxone attenuated hydrocodone-induced alterations of GLT-1, xCT, BDNF, mGluR1, TNF-α, and HMGB1 expression in these brain regions.
Discussion & Conclusions: These findings suggest that the novel β-lactam, MC-100093, has potential preventive effects against opioid overdose.
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