Charleston Alcohol Research Center

Anderson, United States

Charleston Alcohol Research Center

Anderson, United States
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Becker H.C.,Charleston Alcohol Research Center | Becker H.C.,Medical University of South Carolina | Mulholland P.J.,Charleston Alcohol Research Center | Mulholland P.J.,Medical University of South Carolina
Handbook of Clinical Neurology | Year: 2014

Alcohol dependence encompasses a serious medical and societal problem that constitutes a major public health concern. A serious consequence of dependence is the emergence of symptoms associated with the alcohol withdrawal syndrome when drinking is abruptly terminated or substantially reduced. Clinical features of alcohol withdrawal include signs of central nervous system hyperexcitability, heightened autonomic nervous system activation, and a constellation of symptoms contributing to psychologic discomfort and negative affect. The development of alcohol dependence is a complex and dynamic process that ultimately reflects a maladaptive neurophysiologic state. Perturbations in a wide range of neurochemical systems, including glutamate, γ-aminobutyric acid, monoamines, a host of neuropeptide systems, and various ion channels produced by the chronic presence of alcohol ultimately compromise the functional integrity of the brain. These neuroadaptations not only underlie the emergence and expression of many alcohol withdrawal symptoms, but also contribute to enhanced relapse vulnerability as well as perpetuation of uncontrolled excessive drinking. This chapter highlights the hallmark features of the alcohol withdrawal syndrome, and describes neuroadaptations in a wide array of neurotransmitter and neuromodulator systems (amino acid and monoamine neurotransmitter, neuropeptide systems, and various ion channels) as they relate to the expression of various signs and symptoms of alcohol withdrawal, as well as their relationship to the significant clinical problem of relapse and uncontrolled dangerous drinking. © 2014 Elsevier B.V.


Griffin W.C.,Charleston Alcohol Research Center | Nguyen S.A.,Medical University of South Carolina | Deleon C.P.,University of North Carolina at Chapel Hill | Middaugh L.D.,Charleston Alcohol Research Center
Behavioural Pharmacology | Year: 2012

We tested the hypothesis that the irreversible γ-amino butyric acid transaminase inhibitor, γ-vinyl γ-amino butyric acid [vigabatrin (VGB)], would reduce ethanol reinforcement and enhance the discriminative- stimulus effect of ethanol, effectively reducing ethanol intake. The present studies used adult C57BL/6J (B6) mice in well-established operant, two-bottle choice consumption, locomotor activity, and ethanol discrimination procedures to comprehensively examine the effects of VGB on ethanol-supported behaviors. VGB dose-dependently reduced operant responding for ethanol and ethanol consumption for long periods of time. Importantly, a low dose (200 mg/kg) of VGB was selective for reducing ethanol responding without altering the intake of food or water reinforcement. Higher VGB doses (>200mg/kg) reduced ethanol intake, but also significantly increased water consumption and, more modestly, increased food consumption. Although not affecting locomotor activity on its own, VGB interacted with ethanol to reduce the stimulatory effects of ethanol on locomotion. Finally, VGB (200 mg/kg) significantly enhanced the discriminative-stimulus effects of ethanol as evidenced by significant leftward and upward shifts in ethanol generalization curves. Interestingly, VGB treatment was associated with slight increases in blood ethanol concentrations. The reduction in ethanol intake by VGB appears to be related to the ability of VGB to potentiate the pharmacological effects of ethanol. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Stewart S.H.,Charleston Alcohol Research Center | Law T.L.,Medical University of South Carolina | Randall P.K.,Charleston Alcohol Research Center | Newman R.,Medical University of South Carolina
Alcoholism: Clinical and Experimental Research | Year: 2010

Background: Fetal alcohol disorders are preventable, but self-reported alcohol consumption can be misleading and impede effective treatment. Biomarkers represent an alternative method for assessing alcohol use, and this study evaluated the relationship between blood phosphatidylethanol (PEth) and alcohol use in a sample of reproductive age women. Methods: Alcohol use was estimated by validated self-report methods in 80 nonpregnant women ages 18 to 35. PEth was measured by a contracted laboratory using a liquid chromatography-tandem mass spectrometry assay. Regression methods appropriate for the distribution of PEth were used to define its relationship to alcohol consumption during the prior 2 weeks and explore the effects of drinking patterns on this association. Receiver operating characteristic analysis was used to estimate the sensitivity of PEth for various drinking levels at 95% specific cutoffs. Results: PEth had a positive linear association with grams of alcohol consumed (p < 0.001), and was detectable in 93% of subjects consuming an average of 2 or more drinks per day. The relationship between total alcohol consumption and PEth may be stronger in women with recent heavy drinking days. The relationship between drinking and PEth varied considerably between individuals, and sensitivity for a certain amount of drinking was low at a highly specific cutoff concentration. Conclusions: PEth is a highly sensitive indicator of moderate and heavy alcohol consumption in reproductive age women and may complement the use of self-report alcohol screens when additional objective markers of alcohol use are desirable. However, choosing a highly valid cutoff concentration for PEth to differentiate various levels of alcohol consumption may not be feasible. © 2009 by the Research Society on Alcoholism.


Griffin W.C.,Charleston Alcohol Research Center | Novak A.J.,Charleston Alcohol Research Center | Middaugh L.D.,Charleston Alcohol Research Center | Middaugh L.D.,Medical University of South Carolina | Patrick K.S.,Medical University of South Carolina
Pharmacology Biochemistry and Behavior | Year: 2010

The concomitant use of alcohol (EtOH) and the psychotherapeutic agent dl-methylphenidate (MPH) has risen as a consequence of an increase in ADHD diagnoses within the drinking age population. It was recently found that the combination of MPH and EtOH increases the self-report of pleasurable feelings relative to MPH alone. This finding raises concerns regarding the combined abuse liability for these two widely used drugs. The present behavioral study reports on the development of an adult male C57BL/6J (B6) mouse model to further characterize this MPH-EtOH interaction. We examined the effects of MPH on EtOH consumption in a limited access paradigm and EtOH stimulation of locomotor activity. B6 mice consumed about 2. g/kg EtOH daily and MPH dose-dependently reduced drinking. The most effective dose of MPH was 1.25. mg/kg, which produced a 41% decrease in drinking and had no effect on locomotor activity. However, when the 1.25. mg/kg dose of MPH was combined with a stimulatory dose of ethanol (1.75. g/kg) by intraperitoneal injection, there was a significantly enhanced stimulation of locomotor activity. The drug combination increased activity compared to the vehicle or MPH injections by 45% and increased the activity relative to EtOH alone by an additional 25%. The results of the EtOH and MPH interactions observed with the mouse model appear to be behaviorally relevant and suggest several converging mechanisms that may underlie MPH-EtOH interactions. © 2010 Elsevier Inc.


Becker H.C.,Charleston Alcohol Research Center | Becker H.C.,Medical University of South Carolina | Lopez M.F.,Charleston Alcohol Research Center
International Review of Neurobiology | Year: 2016

Despite the high prevalence of alcohol use disorders in the United States, only a relatively small percentage of those afflicted seek treatment. This is further compounded by the fact that there are too few medications available to effectively treat this significant public health problem. The need for identifying and evaluating more effective treatments that aid in preventing relapse and/or tempering risky and harmful alcohol consumption cannot be overstated. Use of animal models represents a critical step in the process of screening, identifying, and informing plans for prioritizing the most promising candidate medications that can be advanced to the next stage of evaluation (clinical laboratory paradigms and controlled clinical trials). Numerous animal models have been developed to study excessive levels of alcohol self-administration. In recent years, a large literature has amassed of studies in which rodent models of dependence have been linked with alcohol self-administration procedures. This chapter focuses on studies employing a dependence model that involves chronic exposure to alcohol vapor by inhalation, which yields in both mice and rats significant escalation of voluntary alcohol consumption. These animal models of dependence and alcohol self-administration have revealed valuable insights about underlying mechanisms that drive excessive drinking. Additionally, this preclinical approach is useful in evaluating the effects of medications on escalated drinking associated with dependence vs more stable levels displayed by nondependent animals. © 2016 Elsevier Inc.


PubMed | Medical University of South Carolina and Charleston Alcohol Research Center
Type: | Journal: International review of neurobiology | Year: 2016

Despite the high prevalence of alcohol use disorders in the United States, only a relatively small percentage of those afflicted seek treatment. This is further compounded by the fact that there are too few medications available to effectively treat this significant public health problem. The need for identifying and evaluating more effective treatments that aid in preventing relapse and/or tempering risky and harmful alcohol consumption cannot be overstated. Use of animal models represents a critical step in the process of screening, identifying, and informing plans for prioritizing the most promising candidate medications that can be advanced to the next stage of evaluation (clinical laboratory paradigms and controlled clinical trials). Numerous animal models have been developed to study excessive levels of alcohol self-administration. In recent years, a large literature has amassed of studies in which rodent models of dependence have been linked with alcohol self-administration procedures. This chapter focuses on studies employing a dependence model that involves chronic exposure to alcohol vapor by inhalation, which yields in both mice and rats significant escalation of voluntary alcohol consumption. These animal models of dependence and alcohol self-administration have revealed valuable insights about underlying mechanisms that drive excessive drinking. Additionally, this preclinical approach is useful in evaluating the effects of medications on escalated drinking associated with dependence vs more stable levels displayed by nondependent animals.


PubMed | Charleston Alcohol Research Center
Type: Journal Article | Journal: Psychopharmacology | Year: 2011

While stress is often proposed to play a significant role in influencing alcohol consumption, the relationship between stress and alcohol is complex and poorly understood. Over several decades, stress effects on alcohol drinking have been studied using a variety of animal models and experimental procedures, yet this large body of literature has generally produced equivocal results.This paper reviews results from animal studies in which alcohol consumption is evaluated under conditions of acute/sub-chronic stress exposure or models of chronic stress exposure. Evidence also is presented indicating that chronic intermittent alcohol exposure serves as a stressor that consequently influences drinking.The effects of various acute/sub-chronic stress procedures on alcohol consumption have generally been mixed, but most study outcomes suggest either no effect or decreased alcohol consumption. In contrast, most studies indicate that chronic stress, especially when administered early in development, results in elevated drinking later in adulthood. Chronic alcohol exposure constitutes a potent stressor itself, and models of chronic intermittent alcohol exposure reliably produce escalation of voluntary alcohol consumption.A complex and dynamic interplay among a wide array of genetic, biological, and environmental factors govern stress responses, regulation of alcohol drinking, and the circumstances in which stress modulates alcohol consumption. Suggestions for future directions and new approaches are presented that may aid in developing more sensitive and valid animal models that not only better mimic the clinical situation, but also provide greater understanding of mechanisms that underlie the complexity of stress effects on alcohol drinking.


PubMed | Charleston Alcohol Research Center
Type: Journal Article | Journal: Psychopharmacology | Year: 2013

Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice.We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus. We also used gas chromatographic methods to measure brain tissue levels of EtOH and the D- and L-isomers of MPH and the metabolite, ethylphenidate (EPH).In discrimination, EtOH (1g/kg) produced a significant leftward shift in the MPH generalization curve (1-2mg/kg) for MPH-trained mice, but no effects of MPH (0.625-1.25mg/kg) on EtOH discrimination in EtOH-trained mice (0-2.5g/kg) were observed. In CPP, the MPH (1.25mg/kg) and EtOH (1.75g/kg) combination significantly increased time on the drug paired side compared to vehicle (30.7%), but this was similar to MPH (28.8%) and EtOH (33.6%). Footslip errors measured in a parallel rod apparatus indicated that the drug combination was very ataxic, with footslips increasing 29.5% compared to EtOH. Finally, brain EtOH concentrations were not altered by 1.75g/kg EtOH combined with 1.25mg/kg MPH. However, EtOH significantly increased D-MPH and L-EPH without changing L-MPH brain concentrations.The enhanced behavioral effects when EtOH is combined with MPH are likely due to the selective increase in brain D-MPH concentrations. These studies are consistent with observations in humans of increased interoceptive awareness of the drug combination and provide new clinical perspectives regarding enhanced ataxic effects of this drug combination.

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