The escalation in ethanol consumption following chronic intermittent ethanol exposure is blunted in mice expressing ethanol-resistant GluN1 or GluN2A NMDA receptor subunits

Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice

“…Consistent with previous studies of female mice and rats [ 82 – 87 ], we found a less robust escalation of voluntary ethanol intake after CIE in females compared with males. This finding could be partially due to a ceiling effect (the female mice begin drinking at levels about three times higher than males before CIE).…”

Altered Activity of Lateral Orbitofrontal Cortex Neurons in Mice following Chronic Intermittent Ethanol Exposure

“…We chose to focus these initial studies on male mice as they show robust and reproducible increases in alcohol drinking and self-administration following exposure to repeated cycles of CIE. In contrast, there is significant variability in CIE-induced drinking in female mice with many studies including our own (Zamudio et al, 2020) showing little to no change in drinking following CIE exposure. This may reflect the higher baseline levels of drinking usually observed in female mice or other as yet identified factors.…”

“…These groups were counterbalanced by ethanol consumption during baseline drinking sessions. The CIE protocol was similar to those used in previous studies (Becker and Lopez, 2004;Zamudio et al 2020). Briefly, all mice were injected with the alcohol dehydrogenase inhibitor pyrazole (1 mmol/kg) prior to being exposed to either air or ethanol vapors for 16 hours per day, Monday through Friday.…”

“…After 8 weeks of baseline drinking in daily 30-minute sessions, they were separated into CIE or Air groups counter-balanced by baseline ethanol consumption. Mice were then exposed to 4 consecutive weeks of CIE or air exposure, as described in previous studies (Becker and Lopez, 2004, den Hartog et al, 2016, Zamudio et al, 2020). CIE exposed animals reached an average blood ethanol concentration of 217.08 mg/dl (SEM=8.75).…”

Aging in nucleus accumbens and its impact on alcohol use disorders

“…In addition, NMDARs are important regulators of ethanol dependence, relapse, withdrawal, and craving ( Krystal, Petrakis, Mason, Trevisan, & D’Souza, 2003 ; Trujillo & Akil, 1995 ). Moreover, several studies showed that intoxicating concentrations of acute ethanol treatment inhibit NMDARs ( Chu, Anantharam, & Treistman, 1995 ; den Hartog et al, 2013 ; Lovinger, White, & Weight, 1990 ; Wirkner, Eberts, Poelchen, Allgaier, & Illes, 2000 ; Zamudio, Gioia, Lopez, Homanics, & Woodward, 2020 ; Zamudio, Smothers, et al, 2020 ), and site-directed mutagenesis identified specific domains in GluN1 and GluN2 NMDAR subunits that influence ethanol inhibition of these receptors ( Honse, Ren, Lipsky, & Peoples, 2004 ; Ronald, Mirshahi, & Woodward, 2001 ; Zamudio, Smothers, et al, 2020 ). For instance, knock-in containing mutated ethanol-resistant GLuN2A subunits showed reduced sensitivity to the sedative and motor-coordinating effect of ethanol when compared to wild-type animals.…”