Alcohol availability during withdrawal gates the impact of alcohol vapor exposure on responses to alcohol cues

Abstract

Background: Chronic intermittent ethanol (CIE) vapor inhalation is a widely used model of alcohol dependence, but the impact of CIE on cue-elicited alcohol seeking is not well understood. Here, we assessed the effects of CIE on alcohol-seeking elicited by previously learned cues, and on acquisition of new cue-alcohol associations. Methods:In Experiment 1, male and female Long Evans rats were first trained in a discriminative stimulus (DS) task, in which one auditory cue (the DS) predicts the availability of 15% ethanol and a control cue (the NS) predicts nothing. Rats then underwent CIE or served as controls. Subsets of each group received access to oral ethanol twice a week during acute withdrawal. After CIE, rats were presented with the DS and NS cues under extinction and retraining conditions to determine whether they would alter their responses to these cues. In Experiment 2, rats underwent CIE prior to training in the DS task. We also assessed alcohol consumption, aversion-resistant drinking, somatic withdrawal symptoms, and behavior in an open field. Results:We found that CIE enhanced behavioral responses to previously learned alcohol cues, but only in rats that received access to alcohol during acute withdrawal. CIE disrupted cue responses in rats that did not. When CIE occurred before cue learning, male rats were slower to develop cue responses and less likely to enter the alcohol port, even though they had received alcohol during acute withdrawal. We also found that CIE increased alcohol consumption and aversion-resistant drinking in male but not female rats.Conclusions: These results suggest that CIE alone does not potentiate the motivational value of alcohol cues, but that an increase in cue responses requires the potentiation of the value of alcohol during acute withdrawal. Further, under some conditions CIE may disrupt responses to previously learned and subsequently acquired alcohol cues.

Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition

“…Here we only assessed the impact of optogenetic inhibition on Pavlovian alcohol-seeking in male rats. A rich prior literature, including our own work, has documented that female rodents, including Long Evans rats, consume more g/kg ethanol on average than male rodents, under both continuous and intermittent access conditions (Li and Lumeng, 1984;Lancaster and Spiegel, 1992;Juárez and De Tomasi, 1999;Priddy et al, 2017;Lorrai et al, 2019;Aguirre et al, 2020;Carpio et al, 2022;Armstrong et al, 2023). While we previously reported no significant sex differences in training trajectories or plateaus during both Pavlovian conditioning for alcohol and training with an alcohol discriminative stimulus (Carpio et al, 2022;Armstrong et al, 2023), it is possible that Pavlovian conditioned responses to alcohol cues in female rats may be differentially impacted by, or resistant to, peri-cue inhibition of the VP.…”