Sean O’Connor

Frontal P300 decrements, alcohol dependence, and antisocial personality disorder.

BACKGROUND The purpose of this study was to examine the independent and interactive effects of alcohol dependence, antisocial personality disorder (ASPD), and age on brain function. METHODS P300 event-related potentials (ERPs) were recorded from 393 alcohol-dependent and 170 non-alcohol-dependent adults while they performed a visual oddball task. The two subject groups were further subdivided based upon age and the presence/absence of ASPD. RESULTS Alcohol dependence was associated with a significant P300 amplitude decrement at anterior electrode sites only. Antisocial personality disorder was also associated with reduced P300 amplitudes at anterior electrode sites; however, the effects were only significant among subjects 30 years of age or younger. To validate this association between ASPD and P300 amplitude a correlational analysis was performed; the correlation between anterior P300 amplitude and the total number of childhood conduct disorder and adult ASPD symptoms was significant. CONCLUSIONS The P300 amplitude decrement found at anterior electrode sites among subjects with ASPD is consistent with the results of numerous ERP, neuroimaging, or neuropsychologic studies of anterior brain function. Our study is unique in suggesting that the effects of ASPD on anterior brain function are best detected during early adulthood. The study also suggests that the detrimental neurophysiologic effects of alcohol dependence predominantly involve the anterior brain.

When What You See Isn’t What You Get: Alcohol Cues, Alcohol Administration, Prediction Error, and Human Striatal Dopamine

BACKGROUND The mesolimbic dopamine (DA) system is implicated in the development and maintenance of alcohol drinking; however, the exact mechanisms by which DA regulates human alcohol consumption are unclear. This study assessed the distinct effects of alcohol-related cues and alcohol administration on striatal DA release in healthy humans. METHODS Subjects underwent 3 PET scans with [(11)C]raclopride (RAC). Subjects were informed that they would receive either an IV Ringers lactate infusion or an alcohol (EtOH) infusion during scanning, with naturalistic visual and olfactory cues indicating which infusion would occur. Scans were acquired in the following sequence: (1) Baseline Scan: Neutral cues predicting a Ringers lactate infusion, (2) CUES Scan: Alcohol-related cues predicting alcohol infusion in a Ringers lactate solution, but with alcohol infusion after scanning to isolate the effects of cues, and (3) EtOH Scan: Neutral cues predicting Ringers, but with alcohol infusion during scanning (to isolate the effects of alcohol without confounding expectation or craving). RESULTS Relative to baseline, striatal DA concentration decreased during CUES, but increased during EtOH. CONCLUSION While the results appear inconsistent with some animal experiments showing dopaminergic responses to alcohols conditioned cues, they can be understood in the context of the hypothesized role of the striatum in reward prediction error, and of animal studies showing that midbrain dopamine neurons decrease and increase firing rates during negative and positive prediction errors, respectively. We believe that our data are the first in humans to demonstrate such changes in striatal DA during reward prediction error.

Intravenous ethanol infusions can mimic the time course of breath alcohol concentrations following oral alcohol administration in healthy volunteers

BACKGROUND 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. METHODS 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 individuals 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. RESULTS 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%]. CONCLUSIONS 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.

Obesity, Smoking, and Frontal Brain Dysfunction

Obesity, smoking, and conduct problems have all been associated with decrements in brain function. However, their additive and interactive effects have rarely been examined. To address the deficiency, we studied P300a and P300b electroencephalographic potentials in 218 women grouped by the presence versus absence of: (1) a BMI > or = 30 kg/m(2); (2) recent smoking; and (3) > or = 2 childhood conduct problems. Analyses revealed smaller P300a and P300b amplitudes over the posterior scalp among recent smokers versus nonsmokers. No corresponding group differences were found in P300 latencies or frontal scalp amplitudes. The most interesting analysis result was an interaction between conduct problems and obesity limited to the frontally generated P300a component: its latency was significantly greater in women with both attributes than in those with either or neither attribute. An exploratory ANOVA, substituting the genotype of a GABRA2 SNP for conduct problems, also demonstrated an interaction with obesity affecting P300a latency. It is hypothesized that conduct problems, and a conduct-problem-associated GABRA2 genotype, decrease the age-of-onset and/or increase the lifetime duration of obesity. As a result, they may potentiate the adverse effects of obesity on frontal white matter and thereby increase P300a latency. Smoking may affect brain function by a different mechanism to reduce posterior scalp P300a and P300b amplitudes while preserving frontal scalp P300a latency and amplitude.

Exposure-Response Relationships during Free-Access Intravenous Alcohol Self-Administration in Nondependent Drinkers: Influence of Alcohol Expectancies and Impulsivity.

Abstract Background: Self-administration is a hallmark of all addictive drugs, including alcohol. Human laboratory models of alcohol self-administration have characterized alcohol-seeking behavior and served as surrogate measures of the effectiveness of pharmacotherapies for alcohol use disorders. Intravenous alcohol self-administration is a novel method that assesses alcohol exposure driven primarily by the pharmacological response to alcohol and may have utility in characterizing unique behavioral and personality correlates of alcohol-seeking and consumption. Methods: This study examined exposure-response relationships for i.v. alcohol self-administration, and the influence of impulsivity and alcohol expectancy, in healthy, nondependent drinkers (n=112). Participants underwent a 2.5-hour free-access i.v. alcohol self-administration session using the Computerized Alcohol Infusion System. Serial subjective response measures included the Drug Effects Questionnaire and Alcohol Urge Questionnaire. To characterize the motivational aspects of alcohol consumption prior to potential acute adaptation, the number of self-infusions in the first 30 minutes of the free-access session was used to classify participants as low- and high-responders. Results: High-responders showed greater subjective responses during i.v. alcohol self-administration compared with low responders, reflecting robust exposure-driven hedonic responses to alcohol. High-responders also reported heavier drinking patterns and lower scores for negative alcohol expectancies on the Alcohol Effects Questionnaire. High-responders also showed higher measures of impulsivity on a delayed discounting task, supporting previous work associating impulsivity with greater alcohol use and problems. Conclusions: These findings indicate that early-phase measures of free-access i.v. alcohol self-administration are particularly sensitive to the rewarding and motivational properties of alcohol and may provide a unique phenotypic marker of alcohol-seeking behavior.

Reliability of striatal [11C]raclopride binding in smokers wearing transdermal nicotine patches

PurposeIn studies where [11C]raclopride (RAC) positron emission tomography (PET) is used to assess changes in striatal dopamine, it is important to control for cognitive states, such as drug craving, that could alter dopamine levels. In cigarette smokers, transdermal nicotine patches (TNP) can control nicotine craving, but the effects of nicotine patches on RAC binding are unknown. Thus, we sought to determine the test-retest reliability of RAC binding in the presence of nicotine patches.MethodsEleven male smokers were scanned twice with RAC on separate days while wearing TNP.ResultsAcross the striatum, test-retest variability was 7.63 ± 5.88; percent change in binding potential was 1.11 ± 9.83; and the intraclass correlation coefficient was 0.91 (p < 0.0001).ConclusionBaseline RAC binding is highly reproducible in smokers wearing nicotine patches. This suggests that TNP are an acceptable method for controlling cigarette craving during studies that utilize RAC to examine changes in dopamine.

Negative urgency, mood induction, and alcohol seeking behaviors.

BACKGROUND Negative urgency, defined as impulsive risk-taking during extreme negative emotional states, is the most important impulsivity-related trait for alcohol-related problems and alcohol dependence. However, how negative urgency imparts risk for alcohol-related problems is not yet well understood. Therefore, the goal of the current study was to examine how negative urgency relates to separable aspects of the emotional experience and alcohol-seeking behaviors. METHODS A total of 34 (19 women) community-dwelling, alcohol-using adults aged 21-32 (mean age=24.86, SD=3.40, 74.3% Caucasian) completed two counterbalanced intravenous alcohol self-administration sessions: one during a neutral mood condition and one during a negative mood condition. RESULTS Negative urgency was associated with 1) greater mood change following negative mood induction (F=4.38, df=15, p=0.002, η2=0.87), but was unrelated to changes in craving or cortisol release in response to mood induction; 2) greater alcohol craving prior to and after an alcohol prime (F=3.27, p=0.02, η2=0.86), but only in the negative and not the neutral mood condition; and 3) higher peak BrAC (F=2.13, df=42, p=0.02, η2=0.48), continuing to increase intoxication level over a longer period (F=3.77, df=42, p<0.001, η2=0.62), and more alcohol seeking (F=21.73, df=22, p<0.001, η2=0.94) throughout the negative session. Negative urgency was associated with overall lower cortisol release. CONCLUSIONS These results highlight the importance of assessing behavioral indicators of negative urgency under mood condition, and suggest that negative urgency may amplify alcohol self-administration through increased negative emotional reactivity to mood events and increased alcohol craving after initial alcohol exposure, leading to maintenance of alcohol related behavior.

Striatal activity correlates with stimulant-like effects of alcohol in healthy volunteers

Individuals who experience greater stimulation and less sedation from alcohol are at increased risk for alcohol-related problems. However, little is known regarding the neurobiological mechanisms underlying subjective response to alcohol. The current study examined the degree to which alcohol-induced brain activation correlates with ratings of stimulation and sedation, using a within-subjects, double-blind, placebo-controlled design. Participants (N = 34 healthy adults with no history of alcohol use disorder) completed three sessions: a calibration session to determine the duration of infusion needed to bring the breath alcohol to 80 mg/dl for each subject, and two counterbalanced fMRI sessions with placebo and alcohol administration. During the fMRI sessions, participants underwent 50 min scans, which included a 10 min baseline period, the IV infusion period needed to bring breath alcohol concentration (BrAC) to a peak 80 mg/dl (on the alcohol session), followed by a post-peak decline period. Participants rated their subjective stimulation and sedation at regular intervals throughout the scan. A priori VOI analyses showed that the time course of stimulation correlated with BOLD signal in the striatum. The time course of sedation did not correlate with BOLD signal in any VOIs. There were no correlations in primary visual cortex, which served as a control. These findings are the first to show that alcohol effects in the striatum are linked to the positive, stimulant-like effects of the drug and advance our understanding of the neurobiological mechanisms underlying individual differences in subjective responses to alcohol, and more broadly, risk for alcohol use disorders.