Browsing by Subject "ethanol"
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Item The Activation and Function of Autophagy in Alcoholic Liver Disease(Bentham Science Publishers, 2017) Khambu, Bilon; Wang, Lin; Zhang, Hao; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of MedicineItem Acute Alcohol and Cognition: Remembering What It Causes Us to Forget(Elsevier, 2019) Van Skike, Candice E.; Goodlett, Charles; Matthews, Douglas B.; Psychology, School of ScienceAddiction has been conceptualized as a specific form of memory that appropriates typically adaptive neural mechanisms of learning to produce the progressive spiral of drug-seeking and drug-taking behavior, perpetuating the path to addiction through aberrant processes of drug-related learning and memory. From that perspective, to understand the development of alcohol use disorders it is critical to identify how a single exposure to alcohol enters into or alters the processes of learning and memory, so that involvement of and changes in neuroplasticity processes responsible for learning and memory can be identified early on. This review characterizes the effects produced by acute alcohol intoxication as a function of brain region and memory neurocircuitry. In general, exposure to ethanol doses that produce intoxicating effects causes consistent impairments in learning and memory processes mediated by specific brain circuitry, whereas lower doses either have no effect or produce a facilitation of memory under certain task conditions. Therefore, acute ethanol does not produce a global impairment of learning and memory, and can actually facilitate particular types of memory, perhaps particular types of memory that facilitate the development of excessive alcohol use. In addition, the effects on cognition are dependent on brain region, task demands, dose received, pharmacokinetics, and tolerance. Additionally, we explore the underlying alterations in neurophysiology produced by acute alcohol exposure that help to explain these changes in cognition and highlight future directions for research. Through understanding the impact acute alcohol intoxication has on cognition, the preliminary changes potentially causing a problematic addiction memory can better be identified.Item Adolescent and Adult Two-Bottle Choice Ethanol Drinking and Adult Impulsivity in Genetically Selected High-Alcohol Preferring Mice(2012-09-20) O'Tousa, David Scott; Grahame, Nicholas J.; Czachowski, Cristine; Boehm II, Stephen L.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 be an inherent underlying biological process that precedes 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. Experiment 1: Selectively bred High-Alcohol Preferring (HAP II) mice, which are shown to be highly impulsive, 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 following 30 days without access, in adulthood. Experiment 2: Adolescent HAP II 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. Adolescent mice consumed significant quantities of ethanol, reaching average blood ethanol concentrations (BECs) of 142 mg/dl in Experiment 1 and 108 mg/dl in Experiment 2. Adult mice reached average BECs of 154 mg/dl in Experiment 2. Mice pre-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. These findings indicate that HAP II 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. Importantly, this research demonstrates that the HAP II mouse is a good candidate for a model of heavy adolescent alcohol consumption.Item Ampicillin/Sulbactam Treatment Modulates NMDA Receptor NR2B Subunit and Attenuates Neuroinflammation and Alcohol Intake in Male High Alcohol Drinking Rats(MDPI, 2020-07-20) Alasmari, Fawaz; Alhaddad, Hasan; Wong, Woonyen; Bell, Richard L.; Sari, Youssef; Psychiatry, School of MedicineExposure to ethanol commonly manifests neuroinflammation. Beta (β)-lactam antibiotics attenuate ethanol drinking through upregulation of astroglial glutamate transporters, especially glutamate transporter-1 (GLT-1), in the mesocorticolimbic brain regions, including the nucleus accumbens (Acb). However, the effect of β-lactam antibiotics on neuroinflammation in animals chronically exposed to ethanol has not been fully investigated. In this study, we evaluated the effects of ampicillin/sulbactam (AMP/SUL, 100 and 200 mg/kg, i.p.) on ethanol consumption in high alcohol drinking (HAD1) rats. Additionally, we investigated the effects of AMP/SUL on GLT-1 and N-methyl-d-aspartate (NMDA) receptor subtypes (NR2A and NR2B) in the Acb core (AcbCo) and Acb shell (AcbSh). We found that AMP/SUL at both doses attenuated ethanol consumption and restored ethanol-decreased GLT-1 and NR2B expression in the AcbSh and AcbCo, respectively. Moreover, AMP/SUL (200 mg/kg, i.p.) reduced ethanol-increased high mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) expression in the AcbSh. Moreover, both doses of AMP/SUL attenuated ethanol-elevated tumor necrosis factor-alpha (TNF-α) in the AcbSh. Our results suggest that AMP/SUL attenuates ethanol drinking and modulates NMDA receptor NR2B subunits and HMGB1-associated pathways.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 Co‐administration of ethanol and nicotine heightens sensitivity to ethanol reward within the nucleus accumbens (NAc) shell and increasing NAc shell BDNF is sufficient to enhance ethanol reward in naïve Wistar rats(Wiley, 2019) Waeiss, Robert A.; Knight, Christopher P.; Engleman, Eric A.; Hauser, Sheketha R.; Rodd, Zachary A.; Psychiatry, School of MedicineAlcohol use disorder most commonly presents as a polydrug disorder where greater than 85% are estimated to smoke. EtOH and nicotine (NIC) co‐abuse or exposure results in unique neuroadaptations that are linked to behaviors that promote drug use. The current experiments aimed to identify neuroadaptations within the mesolimbic pathway produced by concurrent EtOH and NIC exposure. The experiments used four overall groups of male Wistar rats consisting of vehicle, EtOH or NIC alone, and EtOH+NIC. Drug exposure through direct infusion into the posterior ventral tegmental area (pVTA) stimulated release of glutamate and dopamine in the nucleus accumbens (NAc) shell, which was quantified through high‐performance liquid chromatography. Additionally, brain‐derived neurotrophic factor (BDNF) protein levels were measured via enzyme‐linked immunosorbent assay (ELISA). A second experiment investigated the effects of drug pretreatment within the pVTA on the reinforcing properties of EtOH within the NAc shell through intracranial self‐administration (ICSA). The concluding experiment evaluated the effect of NAc shell pretreatment with BDNF on EtOH reward utilizing ICSA within that region. The data indicated that only EtOH+NIC administration into the pVTA simultaneously increased glutamate, dopamine, and BDNF in the NAc shell. Moreover, only pVTA pretreatment with EtOH+NIC enhanced the reinforcing properties of EtOH in the NAc shell. BDNF pretreatment in the NAc shell was also sufficient to enhance the reinforcing properties of EtOH in the NAc shell. The collected data suggest that concurrent EtOH+NIC exposure results in a distinct neurochemical response and neuroadaptations within the mesolimbic pathway that alter EtOH reward.Item Ethanol for preventing preterm birth in threatened preterm labor(Wiley, 2015) Haas, David M.; Morgan, Amanda M.; Deans, Samantha J.; Schubert, Frank P.; Department of Obstetrics and Gynecology, IU School of MedicineBackground Preterm birth is the leading cause of death and disability in newborns worldwide. A wide variety of tocolytic agents have been utilized to delay birth for women in preterm labor. One of the earliest tocolytics utilized for this purpose was ethanol infusion, although this is not generally used in current practice due to safety concerns for both the mother and her baby. Objectives To determine the efficacy of ethanol in stopping preterm labor, preventing preterm birth, and the impact of ethanol on neonatal outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015) and reference lists of retrieved studies. Selection criteria We included randomized and quasi-randomized studies. Cluster-randomized trials and cross-over design trials were not eligible for inclusion. We only included studies published in abstract form if there was enough information on methods and relevant outcomes. Trials were included if they compared ethanol infusion to stop preterm labor versus placebo/control or versus other tocolytic drugs. Data collection and analysis At least two review authors independently assessed studies for inclusion and risk of bias. At least two review authors independently extracted data. Data were checked for accuracy. Main results Twelve trials involving 1586 women met inclusion criteria for this review. One trial did not report on the outcomes of interest in this review. Risk of bias of included studies: The included studies generally were of low quality based on inadequate reporting of methodology. Only three trials had low risk of bias for random sequence generation and one had low risk of bias for allocation concealment and participant blinding. Most studies were either high risk of bias or uncertain in these key areas.Item Ethanol increases glutamate neurotransmission in the posterior ventral tegmental area of female Wistar rats(Wiley, 2012-04) Ding, Zheng-Ming; Engleman, Eric A.; Rodd, Zachary A.; McBride, William J.; Department of Psychiatry, IU School of MedicineBackground— The posterior ventral tegmental area (pVTA) mediates the reinforcing and stimulating effects of ethanol (EtOH). Electrophysiological studies indicated that exposure to EtOH increased glutamate synaptic function in the VTA. The current study determined the neurochemical effects of both acute and repeated EtOH exposure on glutamate neurotransmission in the pVTA. Methods— Adult female Wistar rats were implanted with microdialysis probes in the pVTA. During microdialysis, rats received acute i.p. injection of saline or EtOH (0.5, 1.0 or 2.0 g/kg) and extracellular glutamate levels were measured in the pVTA. The effects of repeated daily injections of EtOH (0.5, 1.0, or 2.0 g/kg) on basal extracellular glutamate concentrations in the pVTA and on glutamate response to a subsequent EtOH challenge were also examined. Results— The injection of 0.5 g/kg EtOH significantly increased (120–125 % of baseline), whereas injection of 2.0 g/kg EtOH significantly decreased (80% of baseline) extracellular glutamate levels in the pVTA. The dose of 1.0 g/kg EtOH did not alter extracellular glutamate levels. Seven repeated daily injections of each dose of EtOH increased basal extracellular glutamate concentrations (from 4.1 ± 0.5 to 9.2 ± 0.5 μM) and reduced glutamate clearance in the pVTA (from 30 ± 2% to 17 ± 2%), but failed to alter glutamate response to a 2.0 g/kg EtOH challenge. Conclusion— The results suggest that the low dose of EtOH can stimulate the release of glutamate in the pVTA, and repeated EtOH administration increased basal glutamate transmission in the pVTA, as a result of reduced glutamate clearance.Item Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets(MDPI, 2013-06-19) Muralidharan, Pooja; Sarmah, Swapnalee; Zhou, Feng C.; Marrs, James A.; Biology, School of ScienceFetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher in low socioeconomic populations. Despite various mechanisms being proposed to explain the etiology of FASD, the molecular targets of ethanol toxicity during development are unknown. Proposed mechanisms include cell death, cell signaling defects and gene expression changes. More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies. These various pathways may interact, producing a wide spectrum of consequences. Detailed understanding of these various pathways and their interactions will facilitate the therapeutic target identification, leading to new clinical intervention, which may reduce the incidence and severity of these highly prevalent preventable birth defects. This review discusses manifestations of alcohol exposure on the developing central nervous system, including the neural crest cells and sensory neural placodes, focusing on molecular neurodevelopmental pathways as possible therapeutic targets for prevention or protection.Item HEAD CIRCUMFERENCE AS PREDICTED BY FACIAL MEASURES IN MOUSE MODEL OF FASD(Office of the Vice Chancellor for Research, 2012-04-13) Timm, Floyd A.; Ward, Richard E.; Wetherill, Leah; Ai, Huisi; Shen, Li; Anthony, Bruce; Zhou, Feng C.Intrauterine exposure to ethanol produces a myriad of anomalies, many tied to the developing brain. Both dose and duration of exposure are suggested to have cumulative effects on brain growth; however, brain volume is difficult to obtain directly, so a commonly used indirect measure of brain volume has been the occipital frontal circumference (OFC) in humans (Malina and Bouchard). In this study, we investigated the relationship of craniofacial measurements and exposure histories against skull circumference in C57BL/6J (Jackson Laboratory) mice. Three alcohol treatment groups were used, which differed in dose of alcohol administered and/or the duration of treatment during gestation. All pups were surrogated at birth with normal dams and received microCT at postnatal day (P) 21. Individual measurement comparisons were made between treatment groups, a control sample of chow fed, and matching groups of pair-fed (isocalorically linked liquid diet). Linear craniofacial measurements were derived from micro-CT images, and a measure of head circumference was constructed using the MxView software (Philips). A multiple linear regression was used to evaluate the facial measurements that best predicted circumference. Variables explored were facial measurements as well as treatment and gender. The model, using a constant, mid facial depth, inner orbital width, and bigonial width predicted 68.8% of variance in circumference (N=164, R2=.688, p=.006). In conclusion, a small set of facial measurements can moderately predict circumference in mice. However, in a small exploratory study, there is an indication that alcohol exposure is a significant factor in the degree to which circumference relates to total brain volume. 2Department of Anthropology Indiana University Purdue University Indianapolis, Indianapolis, Indiana, 46202 3Medical and Molecular Genetics, Indiana University School of Medicine Indianapolis, Indiana, 46202 4Department of Radiology and Imaging Sciences Indiana University School of Medicine, Indianapolis, IN 46202 5Stark Neuroscience Research Institute, Indiana University School of Medicine Indianapolis, Indiana, 46202