Binge ethanol withdrawal: Effects on post-withdrawal ethanol intake, glutamate–glutamine cycle and monoamine tissue content in P rat model

Abstract

Alcohol withdrawal syndrome (AWS) is a medical emergency situation which appears after abrupt cessation of ethanol intake. Decreased GABA-A function and increased glutamate function are known to exist in the AWS. However, the involvement of glutamate transporters in the context of AWS requires further investigation. In this study, we used a model of ethanol withdrawal involving abrupt cessation of binge ethanol administration (4 g/kg/gavage three times a day for three days) using male alcohol-preferring (P) rats. After 48 hours of withdrawal, P rats were re-exposed to voluntary ethanol intake. The amount of ethanol consumed was measured during post-withdrawal phase. In addition, the expression of GLT-1, GLAST and xCT were determined in both medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). We also measured glutamine synthetase (GS) activity, and the tissue content of glutamate, glutamine, dopamine and serotonin in both mPFC and NAc. We found that binge ethanol withdrawal escalated post-withdrawal ethanol intake, which was associated with downregulation of GLT-1 expression in both mPFC and NAc. The expression of GLAST and xCT were unchanged in the ethanol-withdrawal (EW) group compared to control group. Tissue content of glutamate was significantly lower in both mPFC and NAc, whereas tissue content of glutamine was higher in mPFC but unchanged in NAc in the EW group compared to control group. The GS activity was unchanged in both mPFC and NAc. The tissue content of DA was significantly lower in both mPFC and NAc, whereas tissue content of serotonin was unchanged in both mPFC and NAc. These findings provide important information of the critical role of GLT-1 in context of AWS.

SAR and molecular mechanism studies of monoamine oxidase inhibition by selected chalcone analogs

“…The synthesized compounds were initially screened at 10 μM final concentration against recombinant human MAO-A and MAO-B by using 1-methyl-4–(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP) as a nonselective substrate for both MAO-A and B. It is important to note that the K m values for human MAO-A and MAO-B were found to be 88 μM and 101 μM, respectively, and this is in accordance with previously reported values 26 , 27 . The formation of the dihydropyridinium species (MMDP + ) as a MAO-catalyzed oxidation product of MMTP was monitored at 420 nm.…”

Effects of Administered Ethanol and Methamphetamine on Glial Glutamate Transporters in Rat Striatum and Hippocampus

“…(Reissner and Kalivas, 2010). It is noteworthy, that we did not find any significant changes in xCT expression in EtOH compared with water group which is consistent with our previous findings that xCT was not downregulated in binge EtOH drinking (Das et al, 2016). There is possibility that ETOH or MA may induce dysfunction of xCT without affecting its expression.…”

“…In the present study, however, rats were gavaged with EtOH (6 g/kg) for 7 days, which represent the repeated binge dosing paradigm of EtOH (Faingold, 2008). In addition, it has been shown that rats administered EtOH using a binge gavage protocol (4 g/kg, 3 to 4 times a day) reduced GLT-1 expression in the nucleus accumbens, medial prefrontal cortex and striatum (Das et al, 2016; Abulseoud et al, 2014). Interestingly, MA and EtOH exposure has synergistic effect in the downregulation of GLT-1 expression as compared to either drug administered alone.…”

“…Also, chronic EtOH consumption downregulated the expression of major glutamate transporters such as glutamate transporter 1 (GLT-1, its homolog is excitatory amino acid 2) and cystine/glutamate exchanger (xCT) (Rao and Sari, 2014; Sari and Sreemantula, 2012; Aal-Aaboda et al, 2015; Alasmari et al, 2015; Alhaddad et al, 2014; Das et al, 2015). In addition, binge EtOH gavage (4 g/kg, 3 to 4 times a day) decreases the expression of GLT-1 and produces withdrawal signs upon cessation to EtOH exposure (Abulseoud et al, 2014; Das et al, 2016). Glutamate homeostasis is regulated by a number of transporters, including GLT-1, xCT, and glutamate aspartate transporter (GLAST).…”

Effects of Ceftriaxone on Glial Glutamate Transporters in Wistar Rats Administered Sequential Ethanol and Methamphetamine

“…every 2 h × 4) exposure was chosen based on previous studies that showed neurotoxicity and elevation of extracellular glutamate concentration in rat brains (Bowyer et al, 1994 ; Hirata et al, 1995 ; Yamamoto and Zhu, 1998 ; Mark et al, 2004 , 2007 ). The rationale for testing the ethanol binge gavage paradigm was based on recent studies from our laboratory and others (Faingold, 2008 ; Abulseoud et al, 2014 ; Das et al, 2016 ). Control and treated rats were then quickly euthanized by CO 2 inhalation and rapidly decapitated.…”