Indiana University-Purdue University Indianapolis (IUPUI) / Drinking despite aversive consequences, or compulsive drinking, is a criterion of alcohol use disorder and can be modeled in rodents by adding bitter quinine into alcohol. Previous studies have shown the development of quinine-resistant ethanol (EtOH) drinking following a drinking history, but used animals that achieved relatively low blood alcohol levels. Selectively bred crossed High Alcohol Preferring (cHAP) mice average over 250 mg/dl during a two-bottle choice procedure. Compulsive drinking is hypothesized to be D1-receptor mediated via the dorsolateral striatum (DLS). We hypothesized that 2 weeks of free-choice EtOH would lead to quinine resistance and intra-DLS infusion of a D1-antagonist, SCH23390, would attenuate quinine-resistant alcohol drinking with no effect on non-conflicted EtOH drinking. Infusion of SCH23390 into the DMS would not affect quinine-resistant drinking. cHAP mice had guide cannulae placed in the DLS or DMS and had either two weeks (2W) of EtOH and water two-bottle choice or were EtOH naïve (0W). Mice were infused with either SCH23390 or saline immediately prior to one 10% EtOH and water test day and SCH23390 did not disturb alcohol drinking. The following day, we adulterated the EtOH with 0.32-g/L quinine (0.89 mM), and mice received the same microinjection. For animals cannulated in the DLS, 2W history group infused with saline drank more quinine-adulterated EtOH than the 0W saline mice. While SCH23390 infused 0W animals looked no different from saline treated mice, it attenuated quinine + EtOH intake in the 2W animals to the level of 0W animals. Interestingly, DMS-cannulated mice demonstrated similar behavior, with SCH23390 reducing EtOH + quinine consumption, while leaving EtOH consumption undisturbed. Quinine resistance following 2 weeks of free-choice EtOH consumption is attenuated by acute administration of a D1-antagonist in the DLS, suggesting that an alcohol history induces compulsivity and that dopamine contributes to this behavior. This is unique to compulsive drinking, as non-conflicted EtOH drinking was unaffected.

Infusion of a dopamine D1-receptor antagonist into both the dorsolateral and dorsomedial striatum interfered with quinine-resistant alcohol drinking, but not unadulterated alcohol consumption. Dopamine in these two brain regions play a role in compulsive-like alcohol consumption.

Indiana University-Purdue University Indianapolis (IUPUI) / Deficits in impulse control and decision-making have been implicated in the development and maintenance of alcohol use disorders (AUDs). Individuals with AUD often make disadvantageous choices under conditions of probabilistic risk. The Iowa Gambling Task (IGT) is often used to measure risky decision-making, in which impaired individuals tend to favor large, infrequent rewards even when punished for these choices, rather than smaller, safer, and more advantageous rewards. It remains poorly understood if these deficits are behaviors under genetic control and if ethanol intoxication may alter decision-making. High and Low Alcohol Preferring (HAP3 and LAP3, respectively) mice were trained on a novel gambling task to investigate these possible influences. In Experiment 1, HAP3s and LAP3s responded for a 0.1% saccharin solution, choosing between a risky and a safe option. Importantly, choosing the risky option was meant to be ultimately disadvantageous. In Experiment 2, these same HAP3 mice responded for saccharin or saccharin plus 10% ethanol. Contrary to hypothesis, LAP3s preferred the risky option more than HAP3s. Alcohol increased preference for the risky lever, but only in male mice. HAP3 preference for the safe lever may be explained by higher motivation to obtain sweet rewards, or higher overall avidity for responding. Ethanol-induced changes in male risk behavior may be explained by higher androgen levels, but further investigation is required. Similarly, continued research is necessary to optimize a risky decision-making task for both lines, and thus investigate possible genetic differences in risk acceptance that correlate with differences in alcohol intake.

<p>Deficits in impulse control and decision-making have been implicated in the development and maintenance of alcohol use disorders (AUDs). Individuals with AUD often make disadvantageous choices under conditions of probabilistic risk. The Iowa Gambling Task (IGT) is often used to measure risky decision-making, in which impaired individuals tend to favor large, infrequent rewards even when punished for these choices, rather than smaller, safer, and more advantageous rewards. It remains poorly understood if these deficits are behaviors under genetic control and if ethanol intoxication may alter decision-making. High and Low Alcohol Preferring (HAP3 and LAP3, respectively) mice were trained on a novel gambling task to investigate these possible influences. In Experiment 1, HAP3s and LAP3s responded for a 0.1% saccharin solution, choosing between a risky and a safe option. Importantly, choosing the risky option was meant to be ultimately disadvantageous. In Experiment 2, these same HAP3 mice responded for saccharin or saccharin plus 10% ethanol. Contrary to hypothesis, LAP3s preferred the risky option more than HAP3s. Alcohol increased preference for the risky lever, but only in male mice. HAP3 preference for the safe lever may be explained by higher motivation to obtain sweet rewards, or higher overall avidity for responding. Ethanol-induced changes in male risk behavior may be explained by higher androgen levels, but further investigation is required. Similarly, continued research is necessary to optimize a risky decision-making task for both lines, and thus investigate possible genetic differences in risk acceptance that correlate with differences in alcohol intake. </p>

Indiana University-Purdue University Indianapolis (IUPUI) / Habit expression is emerging as a theory of addiction: subjects begin to use drugs to attain positive reinforcing effects but continue to use in spite of negative effects because the behavior becomes habitual, and therefore divorced from its outcome. Many studies have shown that a history of drug and alcohol use lead to expedited acquisition of a habit, but the acute effects of these drugs on behavior is still unknown. Behaviors that result from acute intoxication, such as increased aggression, risky sexual behavior, and impaired judgment, could be interpreted as habitual: actions performed without regard for the outcome. Therefore, we studied the transition from goal-directed to habitual behavior, when a response is made regardless of outcome value, and how acute intoxication of ethanol (EtOH), amphetamine (AMP), nicotine (NIC), and yohimbine (YOH) affect the resulting behavior. Through a series of four experiments, selectively bred crossed High Alcohol Preferring (cHAP) mice were trained on an operant task to self-administer 1% banana solution, which was subsequently devalued via LiCl CTA. EtOH (1 & 1.5 g/kg), AMP (2.0 mg/kg), NIC (0.5 mg/kg), YOH (1.0 mg/kg), or SAL were administered prior to baseline and post-devaluation tests. We found that acute EtOH at 1- and 1.5-g/kg doses facilitated the expression of a habit, whereas all other pretreatments resulted in devaluation. These data may indicate a unique role for EtOH in facilitating the retrieval of habitual over outcome-based associations. This could shed light on why intoxicated individuals display impaired judgment and a mechanism by which relapse after a period of abstinence can occur.

<p>Parkinson’s Disease (PD) and Alcohol Use Disorder (AUD) are neurodegenerative conditions that involve similar neurobiological pathways and affect motivation and reward dysregulations. This project aims to explore whether PD-related insults affect alcohol-related motivation and reward. We utilized paraquat (PQ) exposure as a neurotoxicant-induced model for PD and mice selectively bred for a differential in alcohol preference as a model for genetic and neurobiological susceptibility for high/low alcohol consumption. In Experiment 1, binge-like alcohol drinking after three weeks of PQ exposure (10 mg/kg, i.p. once per week) or saline was assessed in HAP male and female mice. The four-day Drinking in the Dark (DID) procedure was used to induce binge-like alcohol drinking. Dorsal (DS) and ventral (VS) striatal catecholamines were analyzed after DID. Overall, PQ-treated HAP males had significantly lower alcohol intake than saline-treated males. This effect was absent in female HAP mice. Catecholamine quantification showed lower DOPAC levels in VS of PQ-treated vs. saline-treated HAP male mice. Experiment 2 assessed alcohol-induced locomotor sensitization in adult male and female high (HAP) and low-alcohol-preferring (LAP) mice after PQ exposure. Following the same 3 weeks of PQ or saline exposure, mice received 6 sensitization induction days with either 3 g/kg i.p. EtOH or saline. On test day, an alcohol challenge dose of 2 g/kg in all mice was used to determine the expression of locomotor sensitization. PQ exposure had no significant effect on locomotor activity and sensitization. However, PQ-treated mice showed great variability in their alcohol-induced locomotor activity compared to other groups. These data suggest a sex difference in PQ’s effect on alcohol binge-like drinking. However, PQ’s effect on alcohol-induced locomotor sensitization is not conclusive. This project will elucidate potential mechanisms behind PD-related neuropsychiatric comorbid conditions like AUD. Such findings may assist in early diagnosis and treatment refinement, as these comorbidities precede the motor manifestation of PD by decades and significantly impact the quality of life.</p>