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Item Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion(Elsevier, 2017-09) Melón, Laverne C.; Nolan, Zachary T.; Colar, Delphine; Moore, Eileen M.; Boehm II, Stephen L.; Psychology, School of ScienceRecent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABAA receptor subtypes expressing the δ-subunit protein (δ-GABAARs). Indeed, administration of agonists that interact with these δ-GABAARs prior to alcohol access can abolish binge drinking behavior in male mice. These δ-GABAARs have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal gray. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with THIP, an agonist with high selectivity and efficacy at δ-GABAARs. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2h of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of THIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5α-reduced neurosteroids did not disrupt THIP's effects. Analysis of δ-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABAA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that δGABAARs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABAA receptor subtype.Item Adenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice(Elsevier, 2015-08) Fritz, Brandon M.; Boehm II, Stephen L.; Department of Psychology, School of ScienceWe recently observed that the addition of caffeine (a nonselective adenosine receptor antagonist) to a 20% ethanol solution significantly altered the intoxication profile of male C57BL/6J (B6) mice induced by voluntary binge-like consumption in the 'Drinking-in-the-Dark' (DID) paradigm. In the current study, the roles of A1 and A2A adenosine receptor subtypes, specifically, in binge-like ethanol consumption and associated locomotor effects were explored. Adult male B6 mice (PND 60-70) were allowed to consume 20% ethanol (v/v) or 2% sucrose (w/v) for 6days via DID. On day 7, mice received a systemic administration (i.p.) of the A1 antagonist DPCPX (1, 3, 6mg/kg), the A2A antagonist MSX-3 (1, 2, 4mg/kg), or vehicle immediately prior to fluid access in DID. Antagonism of the A1 receptor via DPCPX was found to dose-dependently decrease binge-like ethanol intake and associated blood ethanol concentrations (p's<0.05), although no effect was observed on sucrose intake. Antagonism of A2A had no effect on ethanol or sucrose consumption, however, MSX-3 elicited robust locomotor stimulation in mice consuming either solution (p's<0.05). Together, these findings suggest unique roles for the A1 and A2A adenosine receptor subtypes in binge-like ethanol intake and its associated locomotor effects.Item Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance(Ingenta, 2017-07-07) Gao, Bin; Xu, Ming-Jiang; Bertola, Adeline; Wang, Hua; Zhou, Zhou; Liangpunsakul, Suthat; Medicine, School of MedicineAlcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and to test for therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.Item Binge and High-Intensity Drinking – Associations with Intravenous Alcohol Self-Administration and Underlying Risk Factors(Wiley, 2022) Plawecki, Martin H.; Boes, Julian; Wetherill, Leah; Kosobud, Ann E.K.; Stangl, Bethany L.; Ramchandani, Vijay A.; Zimmermann, Ulrich S.; Nurnberger, John I., Jr.; Schuckit, Marc; Edenberg, Howard J.; Pandey, Gayathri; Kamarajan, Chella; Porjesz, Bernice; Foroud, Tatiana; O’Connor, Sean; Psychiatry, School of MedicineSome styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.Item Binge drinking trajectories across adolescence and early adulthood: Associations with genetic influences for dual-systems impulsive personality traits, alcohol consumption, and alcohol use disorder(medRxiv, 2024-10-16) Miller, Alex P.; Spychala, Kellyn M.; Slutske, Wendy S.; Fromme, Kim; Gizer, Ian R.; Psychiatry, School of MedicineBinge drinking is a relatively common pattern of alcohol use among youth with normative frequency trajectories peaking in emerging and early adulthood. Frequent binge drinking is a critical risk factor for not only the development of alcohol use disorders (AUDs) but also increased odds of alcohol-related injury and death, and thus constitutes a significant public health concern. Changes in binge drinking across development are strongly associated with changes in impulsive personality traits (IPTs) which have been hypothesized as intermediate phenotypes associated with genetic risk for heavy alcohol use and AUD. The current study sought to examine the extent to which longitudinal changes in binge drinking and intoxication frequency across adolescence and early adulthood are associated with genetic influences underlying dual-systems IPTs (i.e., top-down [lack of self-control] and bottom-up [sensation seeking and urgency] constructs) alongside genetic risk for alcohol consumption and AUD. Associations were tested using conditional latent growth curve polygenic score (PGS) models in three independent longitudinal samples (N=10,554). Results suggested consistent significant and independent associations across all samples between sensation seeking PGSs and model intercepts (i.e., higher frequency of binge drinking at first measurement occasion) and alcohol consumption PGSs and model slopes (i.e., steeper increases toward peak binge drinking frequency). Urgency PGSs were not significantly associated with changes in binge drinking or intoxication frequency. Collectively, these findings highlight the role of unique but correlated IPT and alcohol-specific genetic factors in the emergence and escalation of binge drinking during adolescence and early adulthood.Item ChREBP, SIRT1 and ethanol metabolism– a complicated network in alcohol-induced hepatic steatosis.(Wiley, 2015-10) Liangpunsakul, Suthat; Department of Medicine, IU School of MedicineItem Concomitant Caffeine Increases Binge Consumption of Ethanol in Adolescent and Adult Mice, But Produces Additive Motor Stimulation Only in Adolescent Animals(Wiley, 2016-06) Fritz, Brandon M.; Quoilin, Caroline; Kasten, Chelsea R.; Smoke, Michael; Boehm, Stephen L., II; Psychology, School of ScienceBACKGROUND: Binge co-consumption of highly caffeinated energy drinks with alcohol (ethanol [EtOH]) has become a common practice among adolescents/young adults and has been associated with an increased incidence of hazardous behaviors. Animal models are critical in advancing our understanding the neurobehavioral consequences of this form of binge drinking. Surprisingly, virtually no work has explored caffeine and EtOH co-consumption or its long-term consequences in adolescent animals. The primary objective of the current study was to extend a previously established mouse model of voluntary binge caffeine and EtOH co-consumption to explore adolescent consumption and responses compared to adults. METHODS: Adolescent and adult male C57BL/6J mice had daily limited access to caffeine (0.03% w/v), EtOH (20% v/v), a combined EtOH/caffeine solution, or water for 14 days via the binge-like drinking paradigm, drinking-in-the-dark (DID). Home cage locomotor activity was measured during DID in a subset of mice. Following DID, all mice rested for 18 days so that adolescents reached adulthood, whereupon all mice underwent 7 days of continuous access 2-bottle choice drinking for 10% (v/v) EtOH or water. RESULTS: Co-consumption with caffeine significantly increased EtOH intake and resultant blood ethanol concentrations in both adolescent and adult mice. In addition, adolescent mice exhibited a uniquely robust locomotor stimulant response to caffeine and EtOH co-consumption. Later EtOH intake and preference was not influenced, however, by prior fluid consumption history via DID. CONCLUSIONS: Together with findings from the human literature, our results suggest that caffeine co-consumption may positively influence binge alcohol consumption in adolescents/young adults. Importantly, this age group may be particularly sensitive to the additive stimulant effects of caffeinated alcohol consumption, an effect which may be related to the high incidence of associated negative outcomes in this population. These observations are particularly concerning considering the heightened plasticity of the adolescent brain.Item Drinking history dependent functionality of the dorsolateral striatum on gating alcohol and quinine-adulterated alcohol front-loading and binge drinking(Elsevier, 2022) Bauer, Meredith R.; McVey, Megan M.; Boehm, Stephen L., II; Psychology, School of ScienceAfter 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.Item Effects of chronic intermittent ethanol exposure and withdrawal on neuroblastoma cell transcriptome(Elsevier, 2020-06) McClintick, Jeanette N.; Thapa, Kriti; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J.; Biochemistry and Molecular Biology, School of MedicineCycles of heavy drinking and abstinence can lead to ethanol abuse disorder. We studied the effects of chronic intermittent ethanol exposure (CIE) over three weeks on neuroblastoma cells, using an ethanol concentration frequently attained in binge drinking (40 mM, 184 mg/dl). There were many changes in gene expression but most were small. CIE affected pathways instrumental in the development or plasticity of neurons, including axonal guidance, reelin signaling and synaptogenesis. Genes involved in dopamine and serotonin signaling were also affected. Changes in transporters and receptors could dampen both NMDA and norepinephrine transmissions. Decreased expression of the GABA transporter SLC6A11 could increase GABA transmission and has been associated with a switch from sweet drinking to ethanol consumption in rats. Ethanol increased stress responses such as unfolded protein response. TGF-β and NFκB signaling were increased. Most of the genes involved in cholesterol biosynthesis were decreased in expression. Withdrawal for 24 h after CIE caused most of the CIE-induced expression changes to move back toward unexposed levels.Item Effects of coadministration of D-Napvsipq [NAP] and D-Sallrsipa [SAL] on spatial learning after developmental alcohol exposure(2013) Wagner, Jennifer Lynne; Goodlett, Charles R.; Neal-Beliveau, Bethany S.; Grahame, Nicholas J.; Powley, T. L. (Terry L.)Despite warnings about the dangers of drinking during pregnancy, little progress has been made in reducing alcohol drinking among women of childbearing age. Even after the recognition of pregnancy, 15% of women continue to drink, 3% of which admit to binge drinking. Because we cannot stop women from drinking during pregnancy, and many children with fetal alcohol spectrum disorders (FASD) are adopted, there is a significant need to develop postnatal interventions that can improve the long-term outcome of children adversely affected by prenatal alcohol exposure. This thesis aims to evaluate one promising new treatment in the rehabilitation or rescue of specific learning deficits long after the damage has occurred. The treatment evaluated herein (40µg D-NAP + 40µg D-SAL) has long been used in the prevention of the detrimental effects of long-term and binge-like alcohol exposures in rodent models of fetal alcohol syndrome and FASD. Until recently this peptide treatment had only been shown to be effective in preventing some of the consequences of alcohol exposure when administered concurrently with the prenatal alcohol exposure. A recent report by Incerti and colleagues (2010c), however, reported that these peptides could completely reverse a profound spatial learning deficit induced by one episode of a heavy binge-like alcohol exposure (5.9g.kg in a single intraperitoneal injection) on gestational day 8 (G8) in C57BL/6 mice. In that report, the peptide treatment was administered starting in late adolescence, beginning three days prior to and throughout water maze training, and the profound deficits in their alcohol-placebo group were completely eliminated in the alcohol-peptide group. There are currently no FDA-approved treatments for FASD. An effective treatment for the cognitive and behavioral dysfunctions suffered by the 1% of people born today could potentially improve the lives of millions of children and adults. The first aim of this thesis was to determine whether the peptide treatment could reverse the significant spatial learning deficits we have demonstrated in adult C57BL/6 mice given high-dose binge-like alcohol exposure (2.5 g/kg in each of two intraperitoneal injections separated by two hours) on postnatal day (P)7. When administered three days prior to and throughout water maze testing (P67-76), the peptide treatment had no effect on spatial learning. The second aim sought to determine whether the same peptide treatment could reverse water maze spatial learning deficits in G8 binge-like exposure models, as reported by Incerti et al. (2010c). For this analysis, the first study used a different binge-like alcohol exposure model that is more commonly used than that employed by the Incerti et al. (2010c) study, namely administration of 2.8g/kg in each of two intraperitoneal injections separated by four hours (Sulik et al., 1981). This model has been shown to produce high peak blood alcohol concentrations and neuroanatomical aberrations in the hippocampal formation and septal regions (Parnell et al., 2009), which have been implicated in learning and memory. Surprisingly, this G8 binge-like alcohol exposure failed to produce a spatial learning deficit, undermining the usefulness of this model in evaluating the peptide effects. In direct contrast to the outcomes of Incerti et al. (2010c), the G8 Webster alcohol exposure was also unable to produce any deficits in acquisition of spatial learning in the Morris water maze. Surprisingly, neither of the heavy binge-like alcohol exposures on G8 were able to produce spatial learning deficits in the Morris water maze. The binge-like alcohol exposure on P7 did yield the expected spatial learning deficit, but the peptide treatment was unsuccessful in recovering water maze learning. These findings fail to support oral administration of 40µg D-NAP and 40 µg D-SAL as a potential therapy for postnatal alcohol-induced spatial learning deficits in adult mice.