Long-Term Alcohol Drinking Reduces the Efficacy of Forced Abstinence and Conditioned Taste Aversion in Crossed High-Alcohol-Preferring Mice

Abstract

Background: Negative outcomes of alcoholism are progressively more severe as the duration of problem of alcohol use increases. Additionally, alcoholics demonstrate tendencies to neglect negative consequences associated with drinking and/or to choose to drink in the immediate presence of warning factors against drinking. The recently derived crossed high-alcohol-preferring (cHAP) mice, which volitionally drink to heavier intoxication (as assessed by blood ethanol [EtOH] concentration) than other alcohol-preferring populations, as well as spontaneously escalating their intake, may be a candidate to explore mechanisms underlying long-term excessive drinking. Here, we hypothesized that an extended drinking history would reduce the ability of 2 manipulations (forced abstinence [FA] and conditioned taste aversion [CTA]) to attenuate drinking.

Methods: Experiment 1 examined differences between groups drinking for either 14 or 35 days, half of each subjected to 7 days of FA and half not, to characterize the potential changes in postabstinence drinking resulting from an extended drinking history. Experiment 2 used a CTA procedure to assess stimulus specificity of the ability of an aversive flavorant to decrease alcohol consumption. Experiment 3 used this taste aversion procedure to assess differences among groups drinking for 1, 14, or 35 days in their propensity to overcome this aversion when the flavorant was mixed with either EtOH or water.

Results: Experiment 1 demonstrated that although FA decreased alcohol consumption in mice with a 14-day drinking history, it failed to do so in mice drinking alcohol for 35 days. Experiment 2 showed that the addition of a flavorant only suppressed alcohol drinking if an aversion to the flavorant was previously established. Experiment 3 demonstrated that an extended drinking history expedited extinction of suppressed alcohol intake caused by a conditioned aversive flavor.

Conclusions: These data show that a history of long-term drinking in cHAP mice attenuates the efficacy of interventions that normally reduce drinking. Analogous to alcoholics who may encounter difficulties in limiting their intake, cHAP mice with long drinking histories are relatively insensitive to both abstinence and signals of harmful consequences. We propose that the cHAP line may be a valid model for adaptations that occur following the extended heavy alcohol drinking.

Keywords: Abstinence; Animal Model; Conditioned Taste Aversion; Escalation; Ethanol.

Figure 1

Time line for taste aversion conditioning (CTA), free-choice alcohol access (EtOH), and Abstinence (Abst.) for Experiments 1–3. In all experiments, the critical ataxia or alcohol drinking testing was conducted on the same calendar day for all groups. In Experiment 3, mice were tested with the CTA flavor on Days 45–46 either mixed with ethanol (CS+/E) or water (CS+), but in both cases, mice had free-choice access to unflavored water during training and testing.

Figure 2

Forced abstinence results in lessened alcohol intake compared to a continuous access group only in mice with a 14-day drinking history. ns = 7–8, * p < 0.05 compared to deprived mice, independent-samples t-test

Figure 3

Adulteration using a CS+, but not a CS−, reduces intake of 10% ethanol in Experiment 2. All subjects are represented once per time interval, data collapsed across consecutive days. n = 13, *** p < .001, mixed-model ANOVA

Figure 4

Ethanol intake per Time Interval (i.e., bihourly Bin) on the first two days of ethanol drinking mixed with the aversive CS+ in Experiment 3. Mice had previously had either 1 day, 14 days, or 35 day of alcohol drinking experience. ns = 10–11, * p < .05 indicates higher intake in 35-Day, one-way ANOVA.

Figure 5

Preference of CS+ solutions assessed against water in Experiment 3. Animals with a 35-day drinking history demonstrate higher CS+/ethanol preferences, and uniquely show CS+/ethanol preferences that are elevated above CS+ in water, than animals with a 14-day or 1- day drinking history. ns = 10–11, * p < .0042 (Bonferroni corrected) compared to control CS+ alone group, independent-samples t-test