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 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 BEC) 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 two manipulations (forced abstinence and conditioned taste aversion) 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 forced abstinence and half not, to characterize potential changes in post-abstinence drinking resulting from an extended drinking history. Experiment 2 used a conditioned taste aversion 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 ethanol or water. Results Experiment 1 demonstrated that although forced abstinence 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 both to abstinence and signals of harmful consequences. We propose that the cHAP line may be a valid model for adaptations that occur following extended heavy alcohol drinking.

Innate and Acquired Quinine‐Resistant Alcohol, but not Saccharin, Drinking in Crossed High–Alcohol‐Preferring Mice

“…An interesting pattern emerges from examining these findings as a whole: the link between intake escalation and development of compulsive drinking. As we have observed previously (O'Tousa and Grahame, ; Oberlin et al., ), alcohol intake escalates in the high‐drinking lines over time. Prior work links this escalation to behavioral tolerance (Matson et al., ), metabolic tolerance (Matson and Grahame, ), and acquired aversion resistance (O'Tousa and Grahame, ).…”

“…As we have observed previously (O'Tousa and Grahame, ; Oberlin et al., ), alcohol intake escalates in the high‐drinking lines over time. Prior work links this escalation to behavioral tolerance (Matson et al., ), metabolic tolerance (Matson and Grahame, ), and acquired aversion resistance (O'Tousa and Grahame, ). That escalation of alcohol intake appears to be associated with the development of compulsivity, which is consistent with recent theories giving escalation of drug intake a central role in the development of pathological self‐administration, with both alcohol (Edwards and Koob, ) and cocaine (Kippin et al., ; Lesscher and Vanderschuren, ).…”

“…These animals reach average BALs of over 250 mg/dl during free‐choice access (Matson and Grahame, ), coming into contact with the BALs reported in humans by Mello and Mendelson. A previous study found that these mice become resistant to conditioned aversive flavors mixed with EtOH following 5 weeks of EtOH consumption (O'Tousa and Grahame, ). Therefore, we hypothesized that they would develop a similar behavior, QR drinking, perhaps in less than 5 weeks.…”

“…In some individuals, alcohol consumption may become inflexible following a history of drinking, whereas other individuals may be innately susceptible to problematic drinking. To begin modeling this behavior in animals, researchers have used a variety of acquired (O'Tousa and Grahame, ) or innate (Hopf et al., ) aversive flavors added directly to alcohol solutions to assess whether these might moderate drinking. Adding quinine, an innately aversive stimulus, to the alcohol solution, assesses the degree to which alcohol intake remains under aversive control.…”

Sex Differences in Motivation to Self‐Administer Alcohol After 2 Weeks of Abstinence in Young‐Adult Heavy Drinkers

“…Following 3 days of deprivation, one congenic strain of C57Bl/10SnY mice also showed decreases in alcohol intake (Salimov et al, 1995). Selectively bred crossed High Alcohol Preferring mice show a decline in drinking after one week of deprivation following shorter term pre-abstinence alcohol access (2 weeks) but not following longer-term access (5 weeks; (O’Tousa and Grahame (2016)).…”