Acute drug effects on habitual and non-habitual responding in crossed high alcohol preferring mice

RATIONALE: Drug reward plays a central role in acquiring drug-seeking behavior. However, subjects may continue using drugs despite negative consequences because self-administration becomes habitual, and divorced from outcome values. Although a history of drug and alcohol use expedite habit acquisition, and in spite of the fact that self-administration leads to intoxication, the acute effects of drugs on habitual responding are not well understood. OBJECTIVES: We sought to observe how acute ethanol and amphetamine affect the balance between habitual and goal-directed behavior, as measured by a fluid-reinforced operant conditioning task. METHODS: Selectively bred crossed high-alcohol-preferring (cHAP) mice were trained on an operant conditioning task reinforced on a variable interval schedule with 1% banana solution, which was subsequently devalued via LiCl pairing in half the animals. Ethanol (1.0 g/kg), amphetamine (2.0 mg/kg), or saline was administered prior to a post-devaluation test. RESULTS: Overall, mice showed habitual behavior, but when divided into high- or low-responding groups based on training response rates, saline-treated, low-responding animals devalued, while saline-treated high-responding animals did not. Furthermore, amphetamine elicited devaluation even in high-responding animals, while ethanol prevented devaluation even in low-responding animals. CONCLUSIONS: These data show that ethanol shifts animals toward behaving habitually. This may illuminate why alcohol-intoxicated individuals display impaired judgment about the relative merits of drinking, and potentially serve as a mechanism by which intoxicated subjects resume previously devalued behaviors, such as comorbid drug use. These findings also show that high variable interval response rates facilitate a shift from goal-directed to habitual behavior

Selected lines and inbred strains. Tools in the hunt for the genes involved in alcoholism

In their quest to elucidate the genetic influences contributing to alcoholism, researchers have long used selected lines and inbred strains of rodents. Selected lines are obtained by repeatedly mating those animals within a population that show extremely high or low values of the desired trait. Inbred strains are generated by mating male and female siblings, irrespective of any particular trait, over several generations. Both of these approaches have provided researchers with extensive knowledge about the genetic and neurobiological mechanisms contributing to alcohol-related traits. However, the use of these models is associated with some limitations, mostly resulting from the inbreeding involved in generating such lines and strains. Nevertheless, these models can offer some advantages over other genetic approaches, such as the analysis of quantitative trait loci or the generation of transgenic and knockout mice

Habit Formation: Implications for Alcoholism Research

Characteristics of individuals with severe alcohol use disorders include heightened cue sensitivity, compulsive seeking, craving, and continued alcohol use in the face of negative consequences. Animal models are useful for understanding behavioral and neurological mechanisms underlying problematic alcohol use. Seeking of operant reinforcers including alcohol is processed by two mechanisms, commonly referred to as “goal-directed” (action-outcome) and “habitual” (stimulus-response). As substance use disorders are characterized by continued use regardless of unfavorable outcomes, it is plausible that drug use causes an unnatural disruption of these mechanisms. We present a critical analysis of literature pertaining to behavioral neuroscience alcoholism research involving habit formation. Traditionally, when operant behavior is unaffected by a loss of subjective value of a reinforcer (devaluation), the behavior is considered habitual. Acquisition of instrumental behavior requires corticostriatal mechanisms that depend heavily on the prefrontal cortex and ventral striatum, whereas practiced behavior is more predominantly controlled by the dorsal striatum. Dopaminergic signaling is necessary for the neurological adaptations involved in stimulus-response action, and drugs of abuse appear to facilitate habitual behavior through high levels of dopamine release. Evidence suggests that the use of alcohol as a reinforcer expedites habit formation, and that a history of alcohol use produces alterations in striatal morphology, aids habit learning for non-psychoactive reinforcers, and promotes alcohol drinking despite aversive adulterants. In this review, we suggest directions for future alcoholism research that seeks to measure action made despite a devalued outcome, including procedural modifications and genotypic, pharmacological, or neurological manipulations. Most alcoholism models currently in use fail to reach substantial blood ethanol concentrations, a shortcoming that may be alleviated through the use of high-drinking rodent lines. Additionally, satiety, one common mechanism of devaluing reinforcers, is not recommended for alcohol research because the psychoactive effects of alcohol depress response rates, mimicking devaluation effects. Overall, further research of habit formation and potentially related perseverative behaviors could be invaluable in discovering genetic variance, traits that correlate with persistent alcohol seeking, implicated neural structures and processes of alcohol use, and eventually novel pharmacological treatment for alcoholism

Pharmacologically relevant intake during chronic, free-choice drinking rhythms in selectively bred high alcohol-preferring mice

Multiple lines of high alcohol-preferring (HAP) mice were selectively bred for their intake of 10% ethanol (v/v) during 24-hour daily access over a 4-week period, with the highest drinking lines exhibiting intakes in excess of 20 g/kg/day. We observed circadian drinking patterns and resulting blood ethanol concentrations (BECs) in the HAP lines. We also compared the drinking rhythms and corresponding BECs of the highest drinking HAP lines to those of the C57BL/6J (B6) inbred strain. Adult male and female crossed HAP (cHAP), HAP replicate lines 1, 2, 3 and B6 mice had free-choice access to 10% ethanol and water for 3 weeks prior to bi-hourly assessments of intake throughout the dark portion of the light-dark cycle. All HAP lines reached and maintained a rate of alcohol intake above the rate at which HAP1 mice metabolize alcohol, and BECs were consistent with this finding. Further, cHAP and HAP1 mice maintained an excessive level of intake throughout the dark portion of the cycle, accumulating mean BEC levels of 261.5 ± 18.09 and 217.9 ± 25.02 mg/dl, respectively. B6 mice drank comparatively modestly, and did not accumulate high BEC levels (53.63 + 8.15 mg/dl). Free-choice drinking demonstrated by the HAP1 and cHAP lines may provide a unique opportunity for modeling the excessive intake that often occurs in alcohol-dependent individuals, and allow for exploration of predisposing factors for excessive consumption, as well as the development of physiological, behavioral and toxicological outcomes following alcohol exposure

DIFFERENCES IN IMPULSIVITY BETWEEN HIGH-ALCOHOL PREFERRING AND LOW-ALCOHOL PREFERRING MICE IN A DRL TASK

poster abstractHigh impulsivity, the propensity to prefer small immediate rewards to larger delayed rewards, is more observable in alcoholics as well as drug addicts than in non-addicts. However, it remains unclear whether impulsivity precedes and potentially causes substance use disorders. Of particular interest to us is whether the high drinkers differ from low drinkers in their ability to perceive time. In this study we examine differences in impulsivity, as measured by a differential reinforcement of low rates of responding (DRL) task, in mice selectively bred for differences in alcohol consumption, High Alcohol Preferring (HAP-II) and Low Alcohol Preferring (LAP-II) mice. In this task, subjects must inhibit instrumental behavior until an unsignaled DRL interval has elapsed. We hypothesize that due to their previously demonstrated impulsivity, the HAPII mice will perform poorly and receive fewer rewards than LAPII mice. We expect that our results will indicate that due to premature responding, HAPII mice will receive fewer rewards than LAPII mice during the DRL task, but obtain more rewards during a basic fixed interval task, when early responding is not punished. Therefore, alcohol naive HAPII mice will be more impulsive than LAPII mice, as measured by the DRL task. This finding suggests impulsivity is a heritable endophenotype that precedes exposure to alcoholism or drugs

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

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

Emotional reactivity to incentive downshift as a correlated response to selection of high and low alcohol preferring mice and an influencing factor on ethanol intake

Losing a job or significant other are examples of incentive loss that result in negative emotional reactions. The occurrence of negative life events is associated with increased drinking (Keyes, Hatzenbuehler, & Hasin, 2011). Further, certain genotypes are more likely to drink alcohol in response to stressful negative life events (Blomeyer et al., 2008; Covault et al., 2007). Shared genetic factors may contribute to alcohol drinking and emotional reactivity, but this relationship is not currently well understood. We used an incentive downshift paradigm to address whether emotional reactivity is elevated in mice predisposed to drink alcohol. We also investigated if ethanol drinking is influenced in High Alcohol Preferring mice that had been exposed to an incentive downshift. Incentive downshift procedures have been widely utilized to model emotional reactivity, and involve shifting a high reward group to a low reward and comparing the shifted group to a consistently rewarded control group. Here, we show that replicate lines of selectively bred High Alcohol Preferring mice exhibited larger successive negative contrast effects than their corresponding replicate Low Alcohol Preferring lines, providing strong evidence for a genetic association between alcohol drinking and susceptibility to the emotional effects of negative contrast. These mice can be used to study the shared neurological and genetic underpinnings of emotional reactivity and alcohol preference. Unexpectedly, an incentive downshift suppressed ethanol drinking immediately following an incentive downshift. This could be due to a specific effect of negative contrast on ethanol consumption or a suppressive effect on consummatory behavior in general. These data suggest that either alcohol intake does not provide the anticipated negative reinforcement, or that a single test was insufficient for animals to learn to drink following incentive downshift. However, the emotional intensity following incentive downshift provides initial evidence that this type of emotional reactivity may be a predisposing factor in alcoholism

Effects of the Selective PDE4B Inhibitor TDP-003 on Ethanol Consumption

poster abstractAlcoholism is a disease that affects about 18 million Americans. Inhibition of drinking behavior can help develop better therapeutic and medical treatments to these people. Phosphodiesterase-4 (PDE4) is an enzyme that helps breakdown cAMP, which in turn decrease alcohol consumption. cHAP mice are known to have a unique strong preference to ethanol. However, it is not yet known whether or not this relatively new strain of mice are affected by known agonists and antagonist neurotransmitters that reduce ethanol consumption in cousin strains. cHAP mice were used in this particular study due to their unique genetic make-up of having an above average preference to ethanol. The mice were trained for ethanol preference for two weeks. Once the cHAPs obtained stable ethanol consumption, the drug TDP-003, which contains the PDE4B subtype inhibitor, was administered in the morning with interval ethanol and water consumption readings every two hours from the time of injection. TDP-003 was given in three separate doses; 0.03ml, 0.1ml, and a 0.3ml mg/k along with a vehicle dose, which served as a control. Once data was collected and analyzed, it was found that there was not a significant effect in the amount of ethanol the cHAPs were consuming with the drug. In order to ensure that this result was not due to an experimental methods design error, the cHAPs were ran for another week on stable ethanol consumption and then injected with rolipram to see if a positive effect occurred. Rolipram is also a PDE4 inhibitor; predominantly affecting the PDE4B subtype. cHAPS were given three separate doses of rolipram, a 0.1ml, 0.25ml, and a 0.5ml mg/k dose, along with a vehicle dose. Once again, there were no significant differences in the amount of ethanol consumption that was consumed; thus implying that TDP-003 did not work

Effects of Intoxicating Free-Choice Alcohol Consumption During Adolescence on Drinking and Impulsivity During Adulthood in Selectively Bred High Alcohol Preferring Mice

Background— Abuse of alcohol during adolescence continues to be a problem, and it has been shown that earlier onset of drinking predicts increased alcohol abuse problems later in life. High levels of impulsivity have been demonstrated to be characteristic of alcoholics, and impulsivity has also been shown to predict later alcohol use in teenage subjects, showing that impulsivity may precede the development of alcohol use disorders. These experiments examined adolescent drinking in a high-drinking, relatively impulsive mouse population, and assessed its effects on adult drinking and adult impulsivity. Methods— Experiment 1: Selectively bred High-Alcohol Preferring (HAPII) mice were given either alcohol (free choice access) or water only for two weeks during middle adolescence or adulthood. All mice were given free choice access to alcohol 30 days later, in adulthood. Experiment 2: Adolescent HAPII mice drank alcohol and water, or water alone, for two weeks, and were then trained to perform a delay discounting task as adults to measure impulsivity. In each experiment, effects of volitional ethanol consumption on later behavior were assessed. We expected adolescent alcohol exposure to increase subsequent drinking and impulsivity. Results— Mice consumed significant quantities of ethanol, reaching average blood ethanol concentrations (BECs) of 142 mg/dl (adolescent) or 154 mg/dl (adult) in Experiment 1. Adolescent mice in experiment 2 reached an average of 108 mg/dl. Mice exposed to alcohol in either adolescence or adulthood showed a transient increase in ethanol consumption, but we observed no differences in impulsivity in adult mice as a function of whether mice drank alcohol during adolescence. Conclusions— These findings indicate that HAPII mice drink intoxicating levels of alcohol during both adolescence and adulthood, and that this volitional intake has long-term effects on subsequent drinking behavior. Nonetheless, this profound exposure to alcohol during adolescence does not increase impulsivity in adulthood, indicating that long-term changes in drinking are mediated by mechanisms other than impulsivity

Selection for High Alcohol Preference Drinking in Mice Results in Heightened Sensitivity and Rapid Development of Acute Functional Tolerance to Alcohol’s Ataxic Effects

Selection for High Alcohol Preference Drinking in Mice Results in Heightened Sensitivity and Rapid Development of Acute Functional Tolerance to Alcohol’s Ataxic Effects Brandon M. Fritz , Nicholas J. Grahame , and Stephen L. Boehm II Indiana Alcohol Research Center and Department of Psychology, Indiana University – Purdue University Indianapolis, Indianapolis, IN 46202 Abstract Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of the current study was to assess this potential correlated response between alcohol preference and AFT in second and third replicate lines of mice selectively bred for high (HAP2&3) and low (LAP2&3) alcohol preference drinking. Male and female mice were tested for development of AFT on a static dowel task which requires that animals maintain balance on a wooden dowel in order to prevent falling. On test day, each mouse received one (1.75g/kg; Experiment 1) or two (1.75g/kg and 2.0g/kg; Experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in Experiment 2, an additional administration after the first regain of balance on the dowel. Blood samples were taken immediately after loss of balance (when BECs were rising) and at recovery (during falling BECs) in Experiment 1, and after first and second recovery in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BECs than LAP mice following the initial injection of ethanol and were therefore more sensitive to its early effects. Furthermore, Experiment 1 detected significantly greater AFT development (BECfalling - BECrising) in HAP mice as compared to LAP mice which occurred within ~30 min, supporting our hypothesis. However, AFT was not different between lines in Experiment 2, indicating that ~30–60 min following alcohol administration, AFT development was similar in both lines. These data show that high alcohol drinking genetically associates with both high initial sensitivity and very early tolerance to the ataxic effects of ethanol