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Effects of novel beta-lactam, MC-100093, and ceftriaxone on astrocytic glutamate transporters and neuroinflammatory factors in nucleus accumbens of C57BL/6 mice exposed to escalated doses of morphine

Sari, Youssef
; 
Swiss, Ghadeer M. S.
; 
Alrashedi, Fatin A.
; 
Baeshen, Kholoud A.
; 
Alshammari, Sultan A.
; 
Alsharari, Shakir D.
; 
Ali, Nemat
; 
Alasmari, Abdullah F.
; 
Alhoshani, Ali
; 
Alameen, Alaa A.
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Journal article
Date
2024-05-23
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Pharmaceutical Sciences
Subject
Drug dependence
 GLT-1
 Locomotor activity
 Opioid
 xCT
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https://scholarshare.temple.edu/handle/20.500.12613/12016
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https://doi.org/10.1016/j.jsps.2024.102108
Abstract
Chronic exposure to opioids can lead to downregulation of astrocytic glutamate transporter 1 (GLT-1), which regulates the majority of glutamate uptake. Studies from our lab revealed that beta-lactam antibiotic, ceftriaxone, attenuated hydrocodone-induced downregulation of GLT-1 as well as cystine/glutamate antiporter (xCT) expression in central reward brain regions. In this study, we investigated the effects of escalating doses of morphine and tested the efficacy of novel synthetic non-antibiotic drug, MC-100093, and ceftriaxone in attenuating the effects of morphine exposure in the expression of GLT-1, xCT, and neuroinflammatory factors (IL-6 and TGF-β) in the nucleus accumbens (NAc). This study also investigated the effects of morphine and betalactams in locomotor activity, spontaneous alternation percentage (SAP) and number of entries in Y maze since opioids have effects in locomotor sensitization. Mice were exposed to moderate dose of morphine (20 mg/kg, i.p.) on days 1, 3, 5, 7, and a higher dose of morphine (150 mg/kg, i.p.) on day 9, and these mice were then behaviorally tested and euthanized on Day 10. Western blot analysis showed that exposure to morphine downregulated GLT-1 and xCT expression in the NAc, and both MC-100093 and ceftriaxone attenuated these effects. In addition, morphine exposure increased IL-6 mRNA and TGF-β mRNA expression, and MC-100093 and ceftriaxone attenuated only the effect on IL-6 mRNA expression in the NAc. Furthermore, morphine exposure induced an increase in distance travelled, and MC-100093 and ceftriaxone attenuated this effect. In addition, morphine exposure decreased the SAP and increased the number of arm entries in Y maze, however, neither MC100093 nor ceftriaxone showed any attenuating effect. Our findings demonstrated for the first time that MC100093 and ceftriaxone attenuated morphine-induced downregulation of GLT-1 and xCT expression, and morphine-induced increase in neuroinflammatory factor, IL-6, as well as hyperactivity. These findings revealed the beneficial therapeutic effects of MC-100093 and ceftriaxone against the effects of exposure to escalated doses of morphine.
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Youssef Sari, Ghadeer M.S. Swiss, Fatin A. Alrashedi, Kholoud A. Baeshen, Sultan A. Alshammari, Shakir D. Alsharari, Nemat Ali, Abdullah F. Alasmari, Ali Alhoshani, Alaa A. Alameen, Wayne E. Childers, Magid Abou-Gharbia, Fawaz Alasmari, Effects of novel beta-lactam, MC-100093, and ceftriaxone on astrocytic glutamate transporters and neuroinflammatory factors in nucleus accumbens of C57BL/6 mice exposed to escalated doses of morphine, Saudi Pharmaceutical Journal, Volume 32, Issue 7, 2024, 102108, ISSN 1319-0164, https://doi.org/10.1016/j.jsps.2024.102108. (https://www.sciencedirect.com/science/article/pii/S1319016424001580)
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King Saud University
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Saudi Pharmaceutical Journal, Vol. 32, Iss. 7
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