Browsing by Subject "alcohol"
Now showing 1 - 10 of 58
Results Per Page
Sort Options
Item ACUTE FUNCTIONAL TOLERANCE TO ETHANOL IN MICE SELECTIVELY BRED FOR HIGH AND LOW ALCOHOL PREFERENCE DRINKING(Office of the Vice Chancellor for Research, 2012-04-13) Fritz, B.M.; Grahame, N.J.; Boehm II, S.L.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 corre-lated response in second and third replicate lines of mice selectively bred for high (HAP2&3) and low (LAP2&3) alcohol preference drinking. We predicted that HAP mice would develop greater AFT to alcohol’s ataxic actions than LAP mice. Male and female HAP2&3 and LAP2&3 mice were tested for development of AFT on a static dowel task. This task requires that animals maintain balance on a wooden dowel in or-der 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 another experiment, an additional administration after the first regain of balance on the dowel. Blood samples were tak-en immediately after loss of balance and regain in Experiment, 1 and after first and second regain in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BACs than LAP mice following the initial injection of ethanol and were therefore more sensitive. Furthermore, the single-injection experiment detected significantly greater AFT development (BAC2-BAC1) in HAP mice as compared to LAP mice, supporting our hypothesis. This study illus-trates the rapidity with which adaptive pharmacodynamic processes can take place which may contribute to excessive alcohol consumption.Item Alcohol intoxication progressively impairs drivers' capacity to detect important environmental stimuli(Elsevier, 2018) Plawecki, Martin Henry; Koskie, Sarah; Kosobud, Ann; Justiss, Michael D.; O'Connor, Sean; Psychiatry, School of MedicineRationale Alcohol intoxication impairs driving skills, leading to an increased frequency of accidents and crash fatalities. Inebriation may specifically impair environmental vigilance, reducing the driver's capacity for attention to stimuli that are relevant to successful navigation. Objectives We examined the separate and interactive effects of breath alcohol concentration (BrAC) and simulated driving scenario on the capacity to correctly identify visual stimuli embedded in the environment. Methods Ten healthy young adult drivers (6 males; 4 females) each performed 4 driving scenarios at each of 3 steady breath alcohol concentration levels (0, 60 and 100 mg/dl). Scenarios were based on speed or distance keeping while navigating a rural 2-lane road in daytime or nighttime conditions. Drivers pressed a button on the steering wheel corresponding to the direction of an arrow (up or down) which appeared briefly on road signs embedded in the environment, either overhead or on the roadside. Results Increasing level of BrAC and subjective scenario difficulty manifested significant, separate, but not interactive influences in association with the number of arrows correctly identified. Significant impairments could be detected at a level of BrAC below the current American limit for legal operation of a motor vehicle. Conclusions Environmental vigilance is subject to impairment by either/both alcohol intoxication and driving conditions.Item Assessing Motivational and Associative Learning Mechanisms Underlying Compulsive Drinking(2021-08) Carron, Claire R.; Grahame, Nicholas; Czachowski, Cristine; Lapish, Christopher; Hopf, FredricContinued consumption of alcohol despite the knowledge of negative consequences is a hallmark of alcohol use disorder (AUD), yet much remains unknown about what motivates these behaviors. Compulsive drinking may require motivational resources that are not necessary when drinking in unchallenged conditions in order to counteract the addition of these negative consequences. Increased sensitivity to drug-paired stimuli via associative learning processes may provide this additional motivation. To evaluate if alcohol-paired stimuli enhance alcohol seeking, selectively bred crossed High Alcohol Preferring mice experienced Pavlovian conditioning procedures with an alcohol unconditioned stimulus. We hypothesized that after repeated pairings, alcohol cues would elicit seeking conditioned responses. Then, to determine if the motivation provided by these cues influenced responding, mice were trained to respond for alcohol and tested in the presence of alcohol cues. Finally, to test if alcohol-paired cues influence compulsive drinking, this same test was repeated with the addition of response-contingent footshock. We hypothesized the cue paired with alcohol would increase responding for alcohol in unchallenged conditions, but especially in challenged conditions, contributing to compulsivity. An auditory stimulus paired with alcohol did elicit enhanced seeking responses, but contrary to hypothesis, we observed no effect of these same cues on instrumental responding. To validate these findings, training and testing procedures must be optimized to ensure conditioning has properly occurred and compulsivity is being appropriately measured.Item Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆9‐Tetrahydrocannabinol in Adolescent Male Mice(Wiley, 2019-11) Smoker, Michael P.; Hernandez, Maribel; Zhang, Yanping; Boehm, Stephen L., II; Psychology, School of ScienceBackground Cannabinoids and their principle psychoactive target, the cannabinoid type 1 receptor (CB1R), impact a number of alcohol‐related properties, and although alcohol and cannabis are often co‐used, particularly in adolescence, few animal models of this phenomenon exist. We modeled the co‐use of alcohol and ∆9‐tetrahydrocannabinol (THC) in adolescent mice using ingestive methods popular during this developmental period in humans, namely binge‐drinking and edible THC. With this model, we assessed levels of use, acute effects, and tolerance to each substance. Methods Adolescent male C57BL/6J mice had daily, limited access to 1 of 2 edible doughs (THC or control), to 1 of 2 fluids (ethanol (EtOH) or water), and in 1 of 2 orders (dough–fluid or fluid–dough). Home cage locomotor activity was recorded both during access and after access. On the day following the final access session, a subset of mice were assessed for functional and metabolic tolerance to alcohol using accelerating rotarod and blood EtOH concentrations, respectively. The remaining mice were assessed for tolerance to THC‐induced hypothermia, and whole‐brain CB1R expression was assessed in all mice. Results EtOH intake was on par with levels previously reported in adolescent mice. Edible THC was well‐consumed, but consumption decreased at the highest dose provided. Locomotor activity increased following EtOH intake and decreased following edible THC consumption, and edible THC increased fluid intake in general. The use of alcohol produced neither functional nor metabolic tolerance to an alcohol challenge. However, the use of edible THC impaired subsequent drug‐free rotarod performance and was associated with a reduction in THC's hypothermic effect. Conclusions Adolescent mice self‐administered both alcohol and edible THC to a degree sufficient to acutely impact locomotor activity. However, only edible THC consumption had lasting effects during short‐term abstinence. Thus, this adolescent co‐use model could be used to explore sex differences in self‐administration and the impact substance co‐use might have on other domains such as mood and cognition.Item Betaine chemistry, roles, and potential use in liver disease(Elsevier, 2016-06) Day, Christopher R.; Kempson, Stephen A.; Department of Cellular & Integrative Physiology, IU School of MedicineBackground Betaine is the trimethyl derivative of glycine and is normally present in human plasma due to dietary intake and endogenous synthesis in liver and kidney. Betaine is utilized in the kidney primarily as an osmoprotectant, whereas in the liver its primary role is in metabolism as a methyl group donor. In both organs, a specific betaine transporter mediates cellular uptake of betaine from plasma. The abundance of both betaine and the betaine transporter in liver greatly exceeds that of other organs. Scope of review The remarkable contributions of betaine to normal human and animal health are summarized together with a discussion of the mechanisms and potential beneficial effects of dietary betaine supplements on liver disease. Major conclusions A significant amount of data from animal models of liver disease indicates that administration of betaine can halt and even reverse progression of the disruption of liver function. Betaine is well-tolerated, inexpensive, effective over a wide range of doses, and is already used in livestock feeding practices. General significance The accumulated data indicate that carefully controlled additional investigations in humans are merited. The focus should be on the long-term use of betaine in large patient populations with liver diseases characterized by development of fatty liver, especially non-alcoholic fatty liver disease and alcoholic liver disease.Item Burden of Substance Abuse-Related Admissions to the Medical ICU(Elsevier, 2019) Westerhausen, Donald; Perkins, Anthony J.; Conley, Joshua; Khan, Babar A.; Farber, Mark; Biostatistics, School of Public HealthBackground Admissions to the ICU related to alcohol, prescription drugs, and illicit drugs are shown to be widespread and costly. In 1993, a study revealed 28% of ICU admissions at Johns Hopkins Hospital were related to substance abuse and accrued 39% of costs. Since then, health-care expenditures have increased, and substance abuse treatment admissions have risen. We conducted a study to provide updated data on ICU utilization and costs related to licit and illicit abuse at a large county hospital in Indianapolis, Indiana. Methods All admissions to the medical ICU at Eskenazi Hospital from March to October 2017 were reviewed. Demographics, reason for admission, relation to substance abuse and specific substance, ICU and hospital length of stay, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, mortality, insurance status, and hospital charges were collected based on chart review. Results A total of 611 admissions generated $74,587,280.35 in charges. A total of 25.7% of admissions related to substance abuse accounted for 23.1% of total charges. Illicit drugs were 13% of total admissions, generating 11% of charges. Alcohol-related admissions were 9.5% of total admissions, generating 7.6% of charges. Prescription drugs were 2.9% of admissions, generating 4.2% of charges. Of the substance abuse admissions, patients were generally men and 40 to 64 years of age, with longer ICU stay, higher APACHE II scores, and higher mortality. Conclusions Substance abuse admissions make up almost a one-quarter of resources used by our ICU. Patients tend to be younger and sicker with a higher risk of death. Identifying and accurately describing the landscape of this current health crisis will help us take appropriate action in the future.Item Caenorhabditis elegans as a model system to identify therapeutics for alcohol use disorders(Elsevier, 2019-06) Katner, Simon N.; Bredhold, Kristin E.; Steagall, Kevin B., III; Bell, Richard L.; Neal-Beliveau, Bethany S.; Cheong, Mi C.; Engleman, Eric A.; Psychiatry, School of MedicineAlcohol use disorders (AUDs) cause serious problems in society and few effective treatments are available. Caenorhabditis elegans (C. elegans) is an excellent invertebrate model to study the neurobiological basis of human behavior with a conserved, fully tractable genome, and a short generation time for fast generation of data at a fraction of the cost of other organisms. C. elegans demonstrate movement toward, and concentration-dependent self-exposure to various psychoactive drugs. The discovery of opioid receptors in C. elegans provided the impetus to test the hypothesis that C. elegans may be used as a medications screen to identify new AUD treatments. We tested the effects of naltrexone, an opioid antagonist and effective treatment for AUDs, on EtOH preference in C. elegans. Six-well agar test plates were prepared with EtOH placed in a target zone on one side and water in the opposite target zone of each well. Worms were treated with naltrexone before EtOH preference testing and then placed in the center of each well. Wild-type worms exhibited a concentration-dependent preference for 50, 70 and 95% EtOH. Naltrexone blocked acute EtOH preference, but had no effect on attraction to food or benzaldehyde in wild-type worms. Npr-17 opioid receptor knockout mutants did not display a preference for EtOH. In contrast, npr-17 opioid receptor rescue mutants exhibited significant EtOH preference behavior, which was attenuated by naltrexone. Chronic EtOH exposure induced treatment resistance and compulsive-like behavior. These data indicate that C. elegans can serve as a model system to identify compounds to treat AUDs.Item Caffeinated Alcoholic Beverages – An Emerging Trend in Alcohol Abuse(OMICS, 2013-08) Franklin, Kelle M.; Hauser, Sheketha R.; Bell, Richard L.; Engleman, Eric A.; Department of Psychiatry, IU School of MedicineAlcohol use disorders are pervasive in society and their impact affects quality of life, morbidity and mortality, as well as individual productivity. Alcohol has detrimental effects on an individual’s physiology and nervous system, and is associated with disorders of many organ and endocrine systems impacting an individual’s health, behavior, and ability to interact with others. Youth are particularly affected. Unfortunately, adolescent usage also increases the probability for a progression to dependence. Several areas of research indicate that the deleterious effects of alcohol abuse may be exacerbated by mixing caffeine with alcohol. Some behavioral evidence suggests that caffeine increases alcohol drinking and binge drinking episodes, which in turn can foster the development of alcohol dependence. As a relatively new public health concern, the epidemiological focus has been to establish a need for investigating the effects of caffeinated alcohol. While the trend of co-consuming these substances is growing, knowledge of the central mechanisms associated with caffeinated ethanol has been lacking. Research suggests that caffeine and ethanol can have additive or synergistic pharmacological actions and neuroadaptations, with the adenosine and dopamine systems in particular implicated. However, the limited literature on the central effects of caffeinated ethanol provides an impetus to increase our knowledge of the neuroadaptive effects of this combination and their impact on cognition and behavior. Research from our laboratories indicates that an established rodent animal model of alcoholism can be extended to investigate the acute and chronic effects of caffeinated ethanol.Item Chronic Ethanol Drinking by Alcohol-preferring Rats Increases the Sensitivity of the Mesolimbic Dopamine System to the Reinforcing and Stimulating Effects of Cocaine(2013-08-20) Oster, Scott M.; Murphy, James M.; Rodd, Zachary A.; Goodlett, Charles R.; Kinzig, Kimberly P.; Czachowski, Cristine; Hazer, JohnAlcohol and cocaine are commonly co-abused drugs, and those meeting criteria for both cocaine and alcohol use disorders experience more severe behavioral and health consequences than those with a single disorder. Chronic alcohol (ethanol) drinking increased the reinforcing and dopamine (DA) neuronal stimulating effects of ethanol within mesolimbic regions of the central nervous system (CNS) of alcohol-preferring (P) rats. The objectives of the current study were to determine if chronic continuous ethanol drinking produced: (1) alterations in the sensitivity of the nucleus accumbens shell (AcbSh) to the reinforcing effects of cocaine, (2) changes in the magnitude and time course of the local stimulating effects of cocaine on posterior ventral tegmental area (pVTA) DA neurons, and (3) a persistence of alterations in the stimulating effects of cocaine after a period of protracted abstinence. Female P rats received continuous, free-choice access to water and 15% v/v ethanol for at least 10 wk (continuous ethanol-drinking; CE) or access to water alone (ethanol-naïve; N). A third group of rats received the same period of ethanol access followed by 30 d of protracted abstinence from ethanol (ethanol-abstinent; Ab). CE and Ab rats consumed, on average, 6-7 g/kg/d of ethanol. Animals with a single cannula aimed at the AcbSh responded for injections of cocaine into the AcbSh during four initial operant sessions. Cocaine was not present in the self-infused solution for the subsequent three sessions, and cocaine access was restored during one final session. Animals with dual ipsilateral cannulae aimed at the AcbSh and the pVTA were injected with pulsed microinfusions of cocaine into the pVTA while DA content was collected for analysis through a microdialysis probe inserted into the AcbSh. During the initial four sessions, neither CE nor N rats self-infused artificial cerebrospinal fluid (aCSF) or 0.1 mM cocaine into the AcbSh. CE, but not N, rats self-administered 0.5 mM cocaine into the AcbSh, whereas both groups self-infused concentrations of 1.0, 2.0, 4.0, or 8.0 mM cocaine. When cocaine access was restored in Session 8, CE rats responded more on the active lever and obtained more infusions of 0.5, 1.0, 2.0, or 4.0 mM cocaine compared to N rats. Microinjection of aCSF into the pVTA did not alter AcbSh DA levels in N, CE, or Ab rats. Microinjections of 0.25 mM cocaine into the pVTA did not significantly alter AcbSh DA levels in N animals, moderately increased DA levels in CE rats, and greatly increased DA levels in Ab rats. Microinjections of 0.5 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals, robustly increased DA levels in CE rats, and did not significantly alter DA levels in Ab rats. Microinjections of 1.0 or 2.0 mM cocaine into the pVTA modestly increased AcbSh DA levels in N animals but decreased DA levels in CE and Ab rats. Overall, long-term continuous ethanol drinking by P rats enhanced both the reinforcing effects of cocaine within the AcbSh and the stimulatory and inhibitory effects of cocaine on pVTA DA neurons. Alterations in the stimulatory and inhibitory effects of cocaine on pVTA DA neurons were not only enduring, but also enhanced, following a period of protracted abstinence from ethanol exposure. Translationally, prevention of chronic and excessive alcohol intake in populations with a genetic risk for substance abuse may reduce the likelihood of subsequent cocaine use.Item Cortical Regulation of the Ability to Resist Temptation for Punishment-Paired Alcohol(Elsevier, 2020-06) Hopf, F. Woodward; Psychiatry, School of Medicine