MC-100093, a synthetic beta-lactam compound, and ceftriaxone modulate nicotine consumption, neuroinflammation and glutamatergic transporters in a nicotine self-administration mouse model.

Abstract

RATIONALE: Tobacco companies reported that electronic cigarette products were developed to reduce the adverse health effects of conventional cigarettes; however, impairments of lung, brain, and kidney are reported in subjects exposed to electronic cigarettes. Both types contain nicotine in varying amounts, raising concerns about nicotine's toxicity in the body. Studies suggest that modulating glutamate transporters with beta-lactam, ceftriaxone, can reduce nicotine intake. OBJECTIVES: We here tested the pharmacological effects of ceftriaxone and MC-100093 as a novel synthetic beta-lactam, which doesn't have antibiotic action, in mouse model of nicotine self-administration. METHODS: Male C57BL/6 mice were exposed to nicotine-self administration for five weeks, and the effects of ceftriaxone and MC-100,093 on nicotine intake were determined in week 5. Brains were collected for determination of changes in glutamatergic system and neuroinflammatory cytokines levels. Blinded in silico study was conducted to determine the binding properties of ceftriaxone and MC-100093 to glutamate transporter 1 (GLT-1). RESULTS: The results revealed that MC-100093 and ceftriaxone reduced nicotine self-administration. Both compounds attenuated nicotine-induced downregulation of glutamate transporters such as GLT-1 and cystine/glutamate antiporter (xCT), and this effect was associated with attenuation of nicotine-induced increase in glutamate content in the nucleus accumbens. Furthermore, MC-100093 and ceftriaxone attenuated nicotine-increased in TNF-α and IL-6, which indicate that both compounds have a neuroprotective effect. Additionally, the in-silico docking study predicted that both MC-100093 and ceftriaxone exhibited acceptable binding properties into GLT-1. CONCLUSION: Together, these data report potential therapeutic effects of MC-100093 targeting glutamate transporters for treating substance use disorders, particularly tobacco-use disorder.