TY - JOUR T1 - <strong>Effects of a novel beta lactam compound, MC-100093, on the expression of glutamate transporters/receptors and ethanol drinking behavior of alcohol preferring rats</strong> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.122.001147 SP - JPET-AR-2022-001147 AU - Hasan Alhaddad AU - Woonyen Wong AU - Magid Abou-Gharbia AU - Wayne Childers AU - Edward Melenski AU - Richard L. Bell AU - Youssef Sari Y1 - 2022/01/01 UR - http://jpet.aspetjournals.org/content/early/2022/09/24/jpet.122.001147.abstract N2 - Chronic ethanol exposure affects the glutamatergic system in several brain reward regions such as the nucleus accumbens (NAc). Our laboratory has shown that chronic exposure to ethanol reduced the expression of glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger transporter (xCT) and, as a result, increased extracellular glutamate concentrations in the NAc of alcohol preferring (P) rats. Moreover, previous study from our laboratory reported that chronic ethanol intake altered the expression of certain metabotropic glutamate receptors in the brain. In addition to central effects, chronic ethanol consumption induced liver injury, which is associated with steatohepatitis. In the present study, we investigated the effects of chronic ethanol consumption in the brain and liver. Male P rats had access to free choice of ethanol and water bottles for five weeks. Chronic ethanol consumption reduced GLT-1 and xCT expression in the NAc shell but not in the NAc core. Furthermore, chronic ethanol consumption increased fat droplet content as well as peroxisome proliferator-activated receptor alpha (PPAR-α) and GLT-1 expression in the liver. Importantly, treatment with the novel beta-lactam compound, MC-100093, reduced ethanol drinking behavior and normalized the levels of GLT-1 and xCT expression in the NAc shell as well as normalized GLT-1 and PPAR-α expression in the liver. In addition, MC100093 attenuated ethanol-induced increases in fat droplet content in the liver. These findings suggest that MC-100093 might be a potential lead compound to attenuate ethanol-induced dysfunction in glutamatergic system and liver injury. Significance Statement This study identified a novel beta-lactam, MC100093, that has upregulatory effects in GLT-1. MC-100093, reduced ethanol drinking behavior and normalized levels of GLT-1 and xCT expression in the NAc shell as well as normalizing GLT-1 and PPAR-α expression in the liver. In addition, MC100093 attenuated ethanol-induced increases in fat droplet content in the liver. ER -