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ABSTRACT: BACKGROUND: Operant responding paradigms quantify a subject's motivation for reward, but such studies employing ingested alcohol cannot assure the same incremental increase in brain exposure to alcohol across subjects because of substantial variability in absorption kinetics. We developed a human progressive ratio (PR) paradigm using the computer-assisted self-infusion of ethanol (CASE) system that overcomes such variability and conducted a pilot study to assess its utility for detecting an interaction of subjects' GABRA2 or GABRG1 genotype and pretreatment with 1 mg of lorazepam (LZ) vs. placebo on their willingness to work for alcohol rewards. METHODS: Twenty healthy, nondependent drinkers, aged 21 to 27, were balanced on rs279871 and rs2350439 single nucleotide polymorphisms in the GABRA2 and GABRG1 genes, respectively. Subjects worked for alcohol, with water as an alternative reinforcer (AR), using a progressive schedule of a task that required constant attention and adapted to both fatigue and drug effects. Testing began 1 hour after pretreatment with 1 mg LZ or placebo in a crossover design. RESULTS: The CASE system performed well, and the constant attention task was perceived as work by all subjects. GABRA2 homozygosity did not significantly predict either breakpoint or cumulative work, whereas a significant GABRG1 genotype by LZ pretreatment interaction for cumulative work was detected (p = 0.04). Breakpoint revealed a weak trend toward pretreatment drug effects (p = 0.11), and a somewhat stronger interaction of LZ pretreatment with GABRG1 genotype (p = 0.06). GABRG1 status revealed a more complex relationship with respect to motivation for alcohol with and without LZ pretreatment; AG and GG individuals worked more for alcohol under both pretreatment conditions, while AA individuals worked more for the AR. CONCLUSIONS: The CASE PR paradigm shows promise as a laboratory method for use in drug development and phenotyping studies.
Alcoholism Clinical and Experimental Research 07/2012; · 3.34 Impact Factor
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ABSTRACT: The instantaneous rate of change of alcohol exposure (slope) may contribute to changes in measures of brain function following administration of alcohol that are usually attributed to breath alcohol concentration (BrAC) acting alone. To test this proposition, a 2-session experiment was designed in which carefully prescribed, constant-slope trajectories of BrAC intersected at the same exposure level and time since the exposure began. This paper presents the methods and limitations of the experimental design.
Individualized intravenous infusion rate profiles of 6% ethanol (EtOH) that achieved the constant-slope trajectories for an individual were precomputed using a physiologically based pharmacokinetic model. Adjusting the parameters of the model allowed each infusion profile to account for the subject's EtOH distribution and elimination kinetics. Sessions were conducted in randomized order and made no use of feedback of BrAC measurements obtained during the session to modify the precalculated infusion profiles. In one session, an individual's time course of exposure, BrAC(t), was prescribed to rise at a constant rate of 6.0 mg% per minute until it reached 68 mg% and then descend at -1.0 mg% per minute; in the other, to rise at a rate of 3.0 mg% per minute. The 2 exposure trajectories were designed to intersect at a BrAC (t = 20 minutes) = 60 mg% at an experimental time of 20 minutes.
Intersection points for 54 of 61 subjects were within prescribed deviations (range of ± 3 mg% and ± 4 minutes from the nominal intersection point).
Results confirmed the feasibility of applying the novel methods for achieving the intended time courses of the BrAC, with technical problems limiting success to 90% of the individuals tested.
Alcoholism Clinical and Experimental Research 04/2012; 36(6):1042-9. · 3.34 Impact Factor
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ABSTRACT: This review focuses on 27 studies employing experimental alcohol self-administration (ASA) in humans which were published between 1989 and 2010. Twelve studies enrolling healthy, non-dependent social drinkers (HSD) were aimed at evaluating physiological and behavioral determinants of alcohol-induced reward or modeling situations of increased risk to develop alcohol use disorders. The remaining 15 studies tested the effect of medications such as naltrexone, nalmefene, nicotine, mecamylamine, varenicline, gabapentin, aripiprazole, and rimonabant on ASA. The participants were either HSD or non-treatment-seeking alcoholics (NTSA). In 25 of these studies, the subjects ingested alcohol orally and reached a mean peak blood alcohol concentration (BAC) during baseline conditions between 43 and 47 mg% (0.043-0.047%). Two recent studies employed computer-assisted self-infusion of ethanol (CASE), where subjects press a button to request multiple sequential alcohol exposures intravenously instead of drinking. This method has been demonstrated to be safe and provides increased experimental control of BAC and keeps subjects blind concerning the amount already self-administered. Peak exposures in the CASE studies ranged from 60 to 80 mg% in HSD and up to 240 mg% in NTSA.
Current topics in behavioral neurosciences. 07/2011; 13:315-53.
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ABSTRACT: The biological mechanisms by which acute stress increases alcohol consumption are unclear. One potential mechanism is that stress acts by altering the pharmacological and subjective effects of alcohol. Acute stress produces a cascade of physiological and psychological effects, each with a distinctive time course. In this study, we investigated whether different phases of response to an acute stress alter the subjective effects of intravenous alcohol, by administering the drug at 2 different times after the stress.
Healthy men (n = 25) participated in 2 sessions: 1 with the Trier Social Stress Test and the other with a nonstressful control task, each followed by infusions of intravenous alcohol (targeting 40 mg% in 5 minutes) and placebo. One group of participants received alcohol within 1 minute of completing the tasks (Alc0, n = 11), followed by placebo 30 minutes later. In the other group (Alc30, n = 14), the order of alcohol and placebo infusions was reversed. Subjective effects (i.e., anxiety, stimulation, want more) and physiological measures (heart rate, blood pressure, salivary cortisol) were measured before and at repeated intervals after the tasks and infusions.
Stress did not change the subjective effects of alcohol in either group. However, when individual differences in alcohol responses were considered, stress differentially altered the stimulant-like and sedative effects of alcohol. Among individuals who exhibited predominantly stimulant responses to alcohol in the nonstressful condition, stress decreased the stimulant-like effects of alcohol and "wanting more." By contrast, among participants who did not report stimulation after alcohol in the control session, stress decreased the sedative effects and increased "want more." In addition, alcohol administered immediately after the Trier Social Stress Test dampened cortisol responses yet prolonged negative subjective responses to the stress.
These findings demonstrate that there are bidirectional relationships between alcohol and stress. Alcohol influences responses to stress, and stress changes reactions to alcohol, depending on an individual's pattern of response to alcohol. This study highlights the fact that stress-alcohol interactions vary among individual drinkers, suggesting that the effects of stress on motivation to drink alcohol may also differ between individuals.
Alcoholism Clinical and Experimental Research 07/2011; 35(10):1794-803. · 3.34 Impact Factor
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Psychopharm Review. 08/2009; 44(9):65–72.
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ABSTRACT: Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject.
This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual's physiology. The peak BrACs (C(max)), times of peak BrAC (T(max)), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol.
The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean C(max), T(max), and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in C(max) and AUC were both 11%, while the mean %difference for T(max) was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%].
Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response.
Alcoholism Clinical and Experimental Research 04/2009; 33(5):938-44. · 3.34 Impact Factor
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ABSTRACT: Acute alcohol effects may differ in social drinkers with a positive family history of alcohol use disorders (FHP) compared to FH negative (FHN) controls.
To investigate whether FHP subjects prefer higher levels of brain alcohol exposure than do FHN controls.
Twenty-two young healthy nondependent social drinkers participated in two identical sessions of computer-assisted self-infusion of ethanol (CASE); the first for practicing the procedures, the second to test hypotheses. All 12 FHP (four women) and ten FHN (three women) participants received a priming exposure, increasing arterial blood alcohol concentration (aBAC) to 30 mg% at 10 min and decreasing it to 15 mg% at 25 min. A 2-h self-administration period followed, during which only the subjects could increase their aBAC by pressing a button connected to a computer controlling the infusion pump. Infusion rate profiles were calculated instantaneously to increase aBAC by precisely 7.5 mg% within 2.5 min after each button press, followed by a steady descent. Subjects were instructed to produce the same alcohol effects as they would do at a weekend party.
The mean and maximum aBAC during the self-administration period and the number of alcohol requests (NOAR) were significantly higher in the FHP vs. FHN participants.
This is the first laboratory experiment demonstrating higher alcohol self-administration in FHP compared to FHN subjects. A practice session increases the sensitivity of CASE experiments for detection of subtle differences in human alcohol self-administration.
Psychopharmacologia 11/2008; 202(4):689-97. · 4.08 Impact Factor
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ABSTRACT: Human alcohol self-administration studies employing oral intake are subject to high variability of the resulting blood alcohol concentrations because of idiosyncrasies of gastrointestinal absorption kinetics among subjects. We sought to improve the subjects' opportunity to control their brain alcohol exposure by computer-assisted i.v. self-administration.
Instead of drinking, subjects could request increments of their arterial blood alcohol concentration (aBAC) of precisely 7.5 mg% at any time they wanted by pressing a button, provided their aBAC would not exceed 100 mg%. The latency between pushing the button and reaching the new aBAC peak was preset to be 2.5 minutes on the first day and was randomly changed to 1.5 or 3.5 minutes on days 2 and 3 in a crossover design. The necessary rate and amount of alcohol infusion was calculated by the software about once every second. Nine healthy social drinkers (4 females/5 males; mean age 25.0 +/- 4.0 year) participated in 3 sessions each. Outcome measures were mean and maximum observed aBAC, and the number of alcohol requests.
Maximum aBAC was 76.5 +/- 26.3 mg% on average over all experiments. When grouping days 2 and 3 according to latency (1.5 vs. 3.5 minutes), maximum aBAC and the number of requests in the session were significantly higher with the faster rise and all 3 outcome measures were significantly correlated between days. No such correlations were found between the first and either of the following days.
These data suggest that CASE is practical and safe, and results in considerable alcohol exposure that can be manipulated with parameters chosen for the incremental exposure. Following 1 practice day, test-retest stability was good, suggesting a potential for use in scientific studies.
Alcoholism Clinical and Experimental Research 08/2008; 32(7):1321-8. · 3.34 Impact Factor
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Eric A Engleman,
Cynthia M Ingraham,
Kelle M Franklin,
Carrie M Keith,
Joseph A McClaren,
Jonathan A Schultz,
Sandra L Morzorati, Sean O'Connor,
Richard J Thielen,
James M Murphy,
William J McBride
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ABSTRACT: The objective of this study was to determine time-course changes in in vivo ethanol (EtOH) concentrations using a novel subcutaneous (s.c.) microdialysis sampling technique. The hypothesis to be tested was that EtOH concentrations in the s.c. fluid would reflect blood EtOH concentrations. If this is the case, then s.c. microdialysis could allow a more detailed analysis of changes in in vivo levels of EtOH under different drinking paradigms.
Adult male and female Wistar rats and male alcohol-preferring (P) rats were used in this study. A loop-style microdialysis probe was designed for s.c. applications. After initial in vitro characterization, probes were implanted under the skin between the shoulder blades. Animals were allowed to recover 4 to 24 hours prior to microdialysis collection (2.0 microl/min flow rate with isotonic saline). In vivo microdialysis experiments were then conducted to determine (i) the extraction fraction (or clearance) using EtOH no-net-flux (NNF) coupled with the alcohol clamp method, (ii) the dose-response and time-course effects after systemic EtOH administration and to compare with blood EtOH levels, and (iii) the time-course changes in EtOH levels during and after an EtOH drinking episode.
In vivo probe recovery (extraction fraction) obtained using the alcohol clamp method was 69 +/- 3%, and was comparable to the in vitro recovery of 73 +/- 2%. For the EtOH dose-response experiment, rats injected i.p. with 0.5, 1.0, or 2.0 g/kg EtOH showed a clear dose-response effect in the s.c. dialysate samples. Peak concentrations (70, 123, and 203 mg%, respectively) were reached by 15 minutes after injection. In an experiment comparing levels of EtOH in s.c. dialysis and arterial blood samples in rats administered 1.0 g/kg EtOH, similar time-course changes in in vivo EtOH concentrations were observed with both i.g. and i.p. EtOH administration. In P rats drinking 15% EtOH during a 1-hour scheduled access period, EtOH levels in s.c. microdialysates rose rapidly over the session and peaked at approximately 50 mg% at 60 to 80 minutes.
Overall, these experiments indicate that s.c. EtOH and blood EtOH concentrations follow a similar time course. Moreover, s.c. microdialysis can be useful as an experimental approach for determining detailed time-course changes in in vivo EtOH concentrations associated with alcohol drinking episodes.
Alcoholism Clinical and Experimental Research 04/2008; 32(3):435-42. · 3.34 Impact Factor
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ABSTRACT: The additive genetic heritability of bipolar EEG coherence in a sample of 305 non-twin sibships comprising 690 individuals (age range 7-65) was estimated. Heritabilities were examined in 6 frequency bands for each of 15 coherence pairs, both interhemispheric and intrahemispheric. The heritabilities of the bipolar EEG coherence ranged from 0.22 to 0.63 in 79 of the 90 phenotypes which had coherences high enough to provide meaningful values for the estimation of heritability. Heritabilities were greatest in the low and high alpha frequency bands, while theta and beta bands had comparable heritabilities. Coherences themselves were greatest in the low and high alpha frequency bands, while theta coherences were somewhat larger than beta. Higher heritability values were not associated with higher coherences. The examination of bivariate genetic correlations suggests that there is a difference between theta and alpha bands in genetic control of interhemispheric coherence.
Biological Psychology 08/2007; 75(3):260-6. · 3.22 Impact Factor
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Yongqiang Tang,
David B Chorlian,
Madhavi Rangaswamy,
Bernice Porjesz,
Lance Bauer,
Samuel Kuperman, Sean O'Connor,
John Rohrbaugh,
Marc Schuckit,
Arthur Stimus,
Henri Begleiter
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ABSTRACT: The EEG bipolar power spectra provide more localization than spectral measures obtained from monopolar referencing strategies, and have been shown to be useful endophenotypes of psychiatric disorders such as alcoholism. We estimated the additive genetic heritability of resting bipolar EEG power spectra in a large sample of non-twin sibling pairs. The corresponding heritabilities ranged between 0.220 and 0.647 and were highly significant at all 38 electrode pairs for theta (3-7 Hz), low-alpha (7-9 Hz), high-alpha (9-12 Hz), low-beta (12-16 Hz), middle-beta (16-20 Hz) and high-beta (20-28 Hz) frequency bands. The heritabilities were the highest in the high-alpha and low-beta bands at most electrode pairs. The heritabilities were most variable across the head in the three beta bands. Other heritability patterns were also identified within each frequency band. Our results suggest that substantial proportions of the variability in the bipolar EEG measures are explained by genetic factors.
International Journal of Psychophysiology 08/2007; 65(1):2-9. · 2.14 Impact Factor
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ABSTRACT: Prescription of the brain's time course of exposure to experimentally administered ethanol can be achieved with intravenous infusion profiles computed from a physiologically-based pharmacokinetic (PBPK) model of alcohol distribution and elimination. Previous parameter estimation employed transformations of an individual's age, height, weight and gender inferred from the literature, with modeling errors overcome with real-time, intermittent feedback. Current research applications, such as ethanol exposures administered during fMRI scanning, require open-loop infusions, thus improved transformation of morphometric measurements.Records of human breath alcohol concentration (BrAC) clamp experiments were analyzed. Optimal, unique PBPK parameters of a model of the distribution and elimination of ethanol were determined for each record and found to be in concordance with parameter values published by other investigators. A linear transformation between the readily measurable physical characteristics or morphometrics, including gender, age, height, weight, and TBW estimates, and the model parameters were then determined in a least squares sense according to the formula theta=F(x)=F(m)x where x=(age height weight TBW)(T)inR(4) and theta =(R(C) V(P) V(B) m(max)k(AT))(T)inR(5).The transformation was then evaluated with several parameter prediction performance measures. A substantial improvement in all error statistics, in relation to an earlier affine transformation that used only body weight as the relevant morphometric was obtained. Deviation from the measured response was reduced from 27 to 20%. Error in parameter estimation was reduced from 109 to 38%. Percent alcohol provided in error was reduced from 46 to 28%. Error in infusion profile estimation was reduced from 55 to 33%.The algorithm described, which optimizes individual pharmacokinetic parameter values and then subsequent extension to a priori prediction, while not unique, can be readily be adapted to other molecules and pharmacokinetic models. This includes those used for distinct purposes, such as automated control of anesthetic agents.
Biomedical Signal Processing and Control 05/2007; 2(2):97-110. · 1.00 Impact Factor
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ABSTRACT: The additive genetic heritability of both monopolar and bipolar EEG spectral power in a sample of 305 non-twin sibships comprising 690 individuals (age range 7-65) was estimated in order to investigate their regional variation. The heritabilities of the bipolar EEG spectral power ranged from 0.10 to 0.63 in 38 electrode-pairs, and those of monopolar power ranged from 0.23 to 0.68 in 19 electrodes in six frequency bands from theta to high beta. The bipolar data shows significantly greater topographic variation compared to that of the monopolar data. The mean of bivariate genetic correlations were consistently lower for the bipolar data and the coefficients of variation consistently higher when compared to those of the monopolar data for each of the frequency bands. The results from the bipolar derivations are in greater accord with genetic findings in brain anatomy and show the possibility of multiple genetic sources for the phenotypic variability of EEG activity.
Behavior Genetics 04/2007; 37(2):302-13. · 2.52 Impact Factor
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ABSTRACT: Objective To evaluate the influence of family history of alcoholism (FHA) on the response of saccadic eye movements to alcohol.Method Saccadic performance was evaluated in 54 healthy adult subjects with a FHA (family history–positive) and 49 controls (family history–negative). Alcohol and placebo sessions were presented in counterbalanced order. Alcohol was administered intravenously to achieve and maintain a target breath alcohol concentration of 60 mg/100 ml (60%) for 160 min in each subject. During each session, saccadic eye movement testing was performed at baseline (before infusion of alcohol) and twice during the steady-state target breath alcohol concentration. The saccadic testing elicited visually guided saccades (VGS) and antisaccades (AS). Saccadic latency and velocity and the percentage of AS errors were quantified and analyzed using multivariate analysis of variance.Results The family history–positive and family history–negative groups showed an overall difference at baseline in AS and VGS latencies and velocities in the alcohol and placebo sessions (p= 0.006). Alcohol delayed saccades such that AS and VGS latencies increased (p= 0.0001) and slowed the execution of saccades such that peak velocities decreased (p= 0.0002). The percentage of AS errors decreased after alcohol administration, but no significant effect of alcohol (alcohol versus placebo session) was observed (p= 0.1). Latency of AS saccades demonstrated a significant overall FHA effect (p= 0.02) and a significant interaction between FHA and response to alcohol over time (p= 0.02).Conclusions Differences in operational characteristics of the saccadic control system are associated with FHA in adult social drinkers, both at baseline and when the brain is exposed to ethanol at 60 mg/100 ml.
Alcoholism Clinical and Experimental Research 04/2006; 26(10):1568 - 1573. · 3.34 Impact Factor
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ABSTRACT: This manuscript represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer/chair was Ting-Kai Li. The presentations were: (1) Introduction to the Symposium, by Ting-Kai Li; (2) ALDH2 polymorphism and alcohol metabolism, by Shih-Jiun Yin; (3) ALDH2 promoter polymorphism and alcohol metabolism, by David W. Crabb; (4) Use of BrAC clamping to estimate alcohol elimination rates: Application to studies of the influence of genetic and environmental determinants, by Sean O'Connor; and (5) Effect of food and food composition on alcohol elimination rates as determined by clamping, by Vijay A. Ramchandani.
Alcoholism Clinical and Experimental Research 04/2006; 25(1):136 - 144. · 3.34 Impact Factor
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ABSTRACT: Researchers studying alcohol absorption and metabolism in humans have been aided by the alcohol clamp method, in which alcohol is administered intravenously, allowing study participants to achieve and maintain a target breath alcohol concentration (BrAC) for an extended period of time. This tool minimizes the variability in BrACs that occurs after alcohol consumption by administering alcohol at a dose and rate that is computed for each person individually. The alcohol clamp can be used to evaluate several influences on alcohol elimination, including gender, ethnicity, genetic variations in alcohol-metabolizing enzymes, and food consumption.
Alcohol research & health: the journal of the National Institute on Alcohol Abuse and Alcoholism 02/2006; 29(4):286-90. · 0.58 Impact Factor
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ABSTRACT: Physiologically-based pharmacokinetic (PBPK) models have been used to describe the distribution and elimination characteristics of intravenous ethanol administration. Further, these models have been used to estimate the ethanol infusion profile required to prescribe a specific breath ethanol concentration time course in a specific human being, providing a platform upon which other pharmacokinetic and pharmacodynamic investigations are based. In these PBPK models, the equivalence of two different peripheral tissue models are shown and issues concerning the mass flow into the liver in comparison with ethanol metabolism in the liver are explained.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:5033-6.
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ABSTRACT: This article summarizes the proceedings of a symposium organized and cochaired by Vijay Ramchandani and Sean O'Connor and presented at the 2004 Research Society on Alcoholism meeting in Vancouver, BC, Canada. The objectives of this symposium were: (1) to provide a rationale for the development and use of the alcohol clamp and the requirements for its use in alcohol challenge studies; (2) to highlight recent studies conducted using the alcohol clamp to identify sources of variation in the pharmacokinetics and pharmacodynamics of alcohol, as well as to address important research questions related to the relationship between the response to alcohol and the risk for alcoholism; and (3) to provide a perspective on progress, address limitations of the clamp, and identify new directions for alcohol challenge research. The symposium began with an introduction and overview of the alcohol clamp, by Vijay Ramchandani. This was followed by 4 presentations that highlighted recent studies conducted using the clamp including: (1) determination of the influence of alcohol dehydrogenase polymorphisms on alcohol elimination rates in a male Jewish population, by Yehuda Neumark; (2) examination of family history of alcoholism, recent drinking history, and levels and rates of administration as determinants of the response to alcohol and risk for alcoholism, by Sean O'Connor; (3) evaluation of the time course of ethanol intoxication on neuroendocrine function in humans, by Ulrich Zimmermann; and (4) a study of the effects of steady-state blood alcohol levels on auditory event-related potentials in rats, by Sandra Morzorati. Harriet de Wit summarized and discussed the research presented at the symposium and provided her perspective on future directions for research using the alcohol clamp.
Alcoholism Clinical and Experimental Research 02/2006; 30(1):155-64. · 3.34 Impact Factor
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John I Nurnberger,
Ryan Wiegand,
Kathleen Bucholz, Sean O'Connor,
Eric T Meyer,
Theodore Reich,
John Rice,
Marc Schuckit,
Lucy King,
Theodore Petti,
Laura Bierut,
Anthony L Hinrichs,
Samuel Kuperman,
Victor Hesselbrock,
Bernice Porjesz
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ABSTRACT: Alcohol dependence tends to aggregate within families. We analyzed data from the family collection of the Collaborative Study on the Genetics of Alcoholism to quantify familial aggregation using several different criterion sets. We also assessed the aggregation of other psychiatric disorders in the same sample to identify areas of possible shared genetic vulnerability.
Age-corrected lifetime morbid risk was estimated in adult first-degree relatives of affected probands and control subjects for selected disorders. Diagnostic data were gathered by semistructured interview (the Semi-Structured Assessment for the Genetics of Alcoholism), family history, and medical records. Rates of illness were corrected by validating interview and family history reports against senior clinicians' all sources best estimate diagnoses. Sex, ethnicity, comorbidity, cohort effects, and site of ascertainment were also taken into account.
Including data from 8296 relatives of alcoholic probands and 1654 controls, we report lifetime risk rates of 28.8% and 14.4% for DSM-IV alcohol dependence in relatives of probands and controls, respectively; respective rates were 37.0% and 20.5% for the less stringent DSM-III-R alcohol dependence, 20.9% and 9.7% for any DSM-III-R diagnosis of nonalcohol nonnicotine substance dependence, and 8.1% and 5.2% for antisocial personality disorder. Rates of specific substance dependence were markedly increased in relatives of alcohol-dependent probands for cocaine, marijuana, opiates, sedatives, stimulants, and tobacco. Aggregation was also seen for panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and major depression.
The risk of alcohol dependence in relatives of probands compared with controls is increased about 2-fold. The aggregation of antisocial personality disorder, drug dependence, anxiety disorders, and mood disorders suggests common mechanisms for these disorders and alcohol dependence within some families. These data suggest new phenotypes for molecular genetic studies and alternative strategies for studying the heterogeneity of alcohol dependence.
Archives of General Psychiatry 01/2005; 61(12):1246-56. · 12.02 Impact Factor
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ABSTRACT: The present study examined the utility of daily naltrexone for decreasing alcohol drinking in hazardous drinkers. Forty-one participants participated in a 10-week trial and received 30 min of brief counseling on the first and second week of treatment, as well as a daily dose of 50 mg of naltrexone throughout the trial. Overall, naltrexone-treated participants did not show the same degree of improvement on drinking outcomes as placebo-treated participants. The placebo group drank fewer drinks per drinking day and achieved more abstinence days than the naltrexone group. Craving was also lower for the placebo group. The groups were not balanced on gender or family history of alcoholism and this may explain the lack of effect of naltrexone on the drinking outcomes.
Addictive Behaviors 09/2004; 29(6):1253-8. · 2.09 Impact Factor
