Drinking history dependent functionality of the dorsolateral striatum on gating alcohol and quinine-adulterated alcohol front-loading and binge drinking.

After an extended alcohol-drinking history, alcohol use can transition from controlled to compulsive, causing deleterious consequences. Alcohol use can be segregated into two distinct behaviors, alcohol seeking and alcohol taking. Expression of habitual and compulsive alcohol seeking depends on the dorsolateral striatum (DLS), a brain region thought to engage after extended alcohol access. However, it is unknown whether the DLS is also involved in compulsive-like alcohol taking. The purpose of this experiment was to identify whether the DLS gates compulsive-like binge alcohol drinking. To ask this question, we gave adult male and female C57BL/6J mice a binge-like alcohol-drinking history, which we have previously demonstrated to produce compulsive-like alcohol drinking (Bauer, McVey, & Boehm, 2021), or a water-drinking history. We then tested the involvement of the DLS on gating binge-like alcohol drinking and compulsive-like quinine-adulterated alcohol drinking via intra-DLS AMPA receptor antagonism. We hypothesized that pharmacological lesioning of the DLS would reduce compulsive-like quinine-adulterated alcohol (QuA) drinking, but not non-adulterated alcohol drinking, in male and female C57BL/6J mice. Three important findings were made. First, compulsive-like alcohol drinking is significantly blunted in cannulated mice. Because of this, we conclude that we were not able to adequately assess the effect of intra-DLS lesioning on compulsive-like alcohol drinking. Second, we found that the DLS gates binge-like alcohol drinking initially, which replicates findings in our previous work (Bauer, McVey, Germano, Zhang, & Boehm, 2022). However, following an extended alcohol history, the DLS no longer drives this behavior. Finally, alcohol and QuA front-loading is DLS-dependent in alcohol-history mice. Intra-DLS NBQX altered these drinking behaviors without altering ambulatory locomotor activity. These data demonstrate the necessity of the DLS in binge-like alcohol drinking before, but not following, an extended binge-like alcohol-drinking history and in alcohol front-loading in alcohol-history mice.

Systemic administration of racemic baclofen reduces both acquisition and maintenance of alcohol consumption in male and female mice.

Baclofen is a GABAB receptor agonist with proposed use as a treatment for alcohol use disorder (AUD). In preclinical studies, racemic baclofen decreases alcohol consumption in both mice and rats; however, there is a significant disparity in the efficacy of the drug across species. We previously demonstrated that baclofen is enantioselective, with the racemic enantiomer successfully reducing binge-like alcohol consumption during Drinking-in-the-Dark (DID) in C57BL/6J (B6) mice, as well as 24-h consumption during two-bottle choice (2BC) preference drinking in replicate 1 High Alcohol Preferring (HAP) mice. Here we extend these findings by investigating the effects of racemic baclofen on the acquisition and maintenance of alcohol consumption, locomotor activity, and saccharin drinking in two different mouse genotypes and drinking paradigms. Adult male and female B6 mice were allowed free access to 20% (v/v) alcohol for 2 h daily in a 14-day DID procedure. Adult male and female replicate 2 HAP (HAP2) mice were allowed 24-h access to 10% (v/v) alcohol versus tap water in a 2BC procedure for 14 days. Systemic injections of baclofen (0.0 or 3.0 mg/kg) were given 3 h into the dark cycle on days 1-5 in alcohol acquisition experiments and days 6-10 in alcohol maintenance experiments. We found that racemic baclofen significantly reduces acquisition of DID and 2BC alcohol drinking in male and female B6 and HAP2 mice, whereas it only significantly reduces the maintenance of DID alcohol intake in B6 mice. Racemic baclofen did not alter home cage locomotor activity but did alter saccharin intake, suggesting it may have nonspecific effects. The current data add to literature suggesting that smaller doses of racemic baclofen may be an effective treatment of AUD. Future work should focus on the longitudinal efficacy of racemic baclofen in high-drinking mouse genotypes to further investigate whether it is effective for those with a genetic predisposition to AUD.

Intra-dorsolateral striatal AMPA receptor antagonism reduces binge-like alcohol drinking in male and female C57BL/6J mice.

The dorsolateral striatum (DLS) is involved in addiction, reward, and alcohol related behaviors. The DLS primarily receives excitatory inputs which are gated by post-synaptic AMPA receptors. We antagonized AMPA receptors in the DLS to investigate how such modulation affects binge-like alcohol drinking in male and female C57BL/6J mice and whether an associated alcohol drinking history alters dorsomedial striatum (DMS) and DLS AMPA receptor expression. We also investigated the effect of intra-DLS NBQX on locomotor activity and saccharin drinking in mice. Mice were allowed free access to 20% alcohol for two hours each day for a total of seven days. Mice received an intra-DLS infusion of one of four concentrations of NBQX (saline, 0.15, 0.5, or 1.5 µg/side), an AMPA receptor antagonist, immediately prior to alcohol access on day 7. Two-hour binge alcohol intakes, locomotor activity, and blood alcohol concentrations were determined. Intra-DLS NBQX reduced binge-like alcohol drinking in a U-shaped manner in male and female mice. Intake predicted blood alcohol concentration, and locomotor activity was not affected. In a follow up experiment, we assessed whether the most effective NBQX concentration for reducing alcohol consumption also reduced saccharin drinking, finding intra-DLS NBQX did not alter saccharin drinking in male and female mice. These data suggest that AMPA receptors in the DLS play a role in the modulation of binge-like alcohol drinking. These findings further validate the importance of the DLS for alcohol related behaviors and alcohol use disorder.

Reinstating Over-Pouring Behavior: Importance of the Imagined Drinking Context.

BACKGROUND: College students significantly over-pour more than a standard drink in a free-pour simulated alcohol-pouring task. Due to this effect, it is likely that much of the self-report alcohol consumption data incorrectly or underreport actual alcohol consumption. Objective: We sought to determine factors that influence over-pouring. Specifically, in two studies we sought to determine the effect of different factors on the amount of fluid subjects pour in a simulated alcohol-pouring task. Methods: Data were collected from 217 undergraduate students (105 subjects in study 1 and 112 different subjects in study 2). In study one, subjects were asked to pour what they consider to be a standard beer for themselves and an unfamiliar peer. In study two subjects were instructed to pour a beer for themself and the experimenter as if they were at an off-campus party. Results: In study one, we found that size of the cup used to pour into significantly impacted the amount of fluid poured. In addition, subjects poured significantly less for themselves than the unfamiliar peer. In study two, the imagined context in which subjects poured significantly increased the amount of fluid poured demonstrating the importance of imagined contextual cues on alcohol use behavior. Conclusions/Importance: Imagined drinking context, presence of an unfamiliar peer, and cup size affect the amount of fluid poured in a simulated alcohol free pour task. Given the various factors that impact free pouring in college students, self-report alcohol data should be considered with caution.

Three Weeks of Binge Alcohol Drinking Generates Increased Alcohol Front-Loading and Robust Compulsive-Like Alcohol Drinking in Male and Female C57BL/6J Mice.

BACKGROUND: Current models of compulsive-like quinine-adulterated alcohol (QuA) drinking in mice, if improved, could be more useful for uncovering the neural mechanisms of compulsive-like alcohol drinking. The purpose of these experiments was to further characterize and improve the validity of a model of compulsive-like QuA drinking in C57BL/6J mice. We sought to determine whether compulsive-like alcohol drinking could be achieved following 2 or 3 weeks of Drinking-in-the-Dark (DID), whether it provides evidence for a robust model of compulsive-like alcohol drinking by inclusion of a water control group and use of a highly concentrated QuA solution, whether repeated QuA exposures alter compulsive-like drinking, and whether there are sex differences in compulsive-like alcohol drinking. METHODS: Male and Female C57BL/6J mice were allowed free access to either 20% alcohol or tap water for 2 hours each day for approximately 3 weeks. After 2 or 3 weeks, the mice were given QuA (500 µM) and the effect of repeated QuA drinking sessions on compulsive-like alcohol drinking was assessed. 3-minute front-loading, 2 hour binge-drinking, and blood alcohol concentrations were determined. RESULTS: Compulsive-like QuA drinking was achieved after 3 weeks, but not 2 weeks, of daily alcohol access as determined by alcohol history mice consuming significantly more QuA than water history mice and drinking statistically nondifferent amounts of QuA than nonadulterated alcohol at baseline. Thirty-minute front-loading of QuA revealed that alcohol history mice front-loaded significantly more QuA than water history mice, but still found the QuA solution aversive. Repeated QuA exposures did not alter these patterns, compulsive-like drinking did not differ by sex, and BACs for QuA drinking were at the level of a binge. CONCLUSIONS: These data suggest that compulsive-like QuA drinking can be robustly achieved following 3 weeks of DID and male and female C57BL/6J mice do not differ in compulsive-like alcohol drinking.

Systemic Administration of the AMPA Receptor Antagonist, NBQX, Reduces Alcohol Drinking in Male C57BL/6J, But Not Female C57BL/6J or High-Alcohol-Preferring, Mice.

BACKGROUND: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are ionotropic glutamate receptors that have been investigated for their role in modulating alcohol consumption. However, little is known about the role of AMPA receptors in the control of binge-like or free-access alcohol drinking in C57BL/6J or in selectively bred high-alcohol-preferring (HAP) mice. The purpose of this experiment was to assess the role of systemic administration of the AMPA receptor antagonist, 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX), on alcohol consumption using a model of binge-like drinking, drinking in the dark (DID) and free-access 2-bottle choice (2BC) in male and female C57BL/6J and HAP mice. METHODS: C57BL/6J mice were allowed free access to 20% (v/v) alcohol for 2 hours each day beginning 3 hours into the dark cycle for 4 days. On day 5, mice were intraperitoneally injected with one of 4 doses of NBQX (0, 3, 10, or 30 mg/kg; n = 10) 15 minutes before alcohol presentation and were given 4-hour alcohol access (extended DID). HAP mice were given 24-hour free access to 10% (v/v) alcohol and water for 19 days. On day 20, mice were intraperitoneally injected with one of 4 doses of NBQX (0, 3, 10, or 30 mg/kg; n = 9) 15 minutes before alcohol and water presentation. RESULTS: In the first 2 hours of DID, at 30 mg/kg, male, but not female C57BL/6J or HAP, mice drank significantly less alcohol compared with controls and 30 mg/kg NBQX did not alter saccharin intake in the males. Although male HAP mice drank significantly less alcohol than female mice following 10 mg/kg NBQX, neither sex exhibited drinking that differed significantly from controls. NBQX did not reduce locomotor behavior at any dose, sex, or genotype. CONCLUSIONS: These data suggest that AMPA receptors play a key role in modulating binge-like alcohol consumption without altering saccharin consumption or general locomotion and that this effect is specific to sex and genotype.