S27 * INNOVATIVE TECHNIQUES IN HUMAN LABORATORY ALCOHOL RESEARCH (2013)

# S27.1 THE COMPUTER-ASSISTED INFUSION SYSTEM (CAIS) FOR EXPERIMENTAL ETHANOL ADMINISTRATION IN HUMANS {#article-title-2}

Ingestion of alcohol leads to substantial variability across subjects in the systemic exposure to alcohol, including that of the brain. Using intravenous infusion bypasses these sources of variability and, together with a physiologically based pharmacokinetic (PBPK) model of alcohol distribution and elimination grants much better control over the time course of arterial blood alcohol concentration (aBAC). Infusion rates are adapted once every 30 seconds to follow an aBAC time profile prescribed by the experimenter. Besides improved control over aBAC, other advantages of i.v. alcohol administration over oral ingestion include safety, since aBAC declines immediately after the infusion is stopped and blinding, since alcohol can be administered without the subject's awareness. Infusion also provides a reliable method for dissociating the response to alcohol administration from demand characteristics such as taste, smell, and familiarity/preference of the source of the alcohol. Initially, these methods were developed to achieve constant aBAC over several hours of experiments testing alcohol effects (alcohol clamping). With more refined methods of modeling, infusion was recently developed for self-administration experiments with free access or operant paradigms requiring work to gain access to alcohol. Results of two self-administration studies will be presented. The computer-assisted infusion system (CAIS), i.e. a software platform enabling for all these types of experiments is now made available to interested researchers.

# S27.2 CHARACTERIZATION OF OPERANT INTRAVENOUS ALCOHOL SELF-ADMINISTRATION IN HUMANS {#article-title-3}

Computer-Assisted Self-infusion of Ethanol (CASE) is a method of intravenous (IV) alcohol administration that allows alcohol self-administration in a laboratory setting, while controlling the breath alcohol concentration (BrAC) using a physiologically-based pharmacokinetic (PBPK) model-based algorithm. The objective of this study was to develop and characterize operant IV alcohol self-administration in non-dependent drinkers using two paradigms: free-access and progressive-ratio. Healthy non-dependent drinkers completed two IV alcohol self-administration sessions, each consisting of a 25-min priming phase followed by a 125-min phase where they could push a button for additional ethanol infusions, using a free-access (FA) schedule (one button press/ infusion) and a progressive ratio (PR) schedule (increasing button presses for infusions). The number of rewards and peak and average BrAC were recorded, as well as the total and average number of button presses and button-press rate for the PR group. Regression analyses assessed effects of drinking history, alcohol sensitivity and personality. Results indicated high degree of within-session correlation among self-administration measures for both paradigms, indicating high internal consistency. In the FA paradigm, self-administration measures were significantly associated with drinks/drinking day, alcohol sensitivity, and reward sensitivity. Alcohol urges following priming were associated with self-administration measures for both OB and PR paradigms and rates of self-infusion were associated with subjective response to alcohol and measures of expectancy and impulsivity. Individuals with higher expectancy of negative alcohol effects and with higher impulsivity showed lower responses on both paradigms. These results indicate that IV self-administration measures reflect drinking history and alcohol sensitivity and expectancy effects.

# S27.3 STUDYING THE ROLE OF FEEDING-RELATED PATHWAYS IN ALCOHOLISM VIA HUMAN LABORATORY STUDIES {#article-title-4}

Feeding-related peptides may play a role in alcohol-related behaviors, including alcohol craving and consumption. We have reported, for example, that anorexigenic peptides such as insulin and thyroid hormones may be associated with alcohol craving and alcohol consumption. More recently, our lab started investigating the possible role of ghrelin in alcoholism. For example, human studies with alcohol-dependent individuals suggest that higher blood levels of the orexigenic gut-brain peptide ghrelin are associated with higher self-reported alcohol craving. Our most recent longitudinal study indicated a significant difference in baseline ghrelin levels between non-abstinent and abstinent subjects, as well as inverse ghrelin's patterns between the two groups during the study. Furthermore, there was a positive significant correlation between baseline ghrelin levels and self-reported alcohol craving. More recently, we performed a human laboratory study in non-treatment seeking heavy drinking alcohol-dependent individuals where subjects are randomized to receive an intravenous (IV) administration of ghrelin 1 microg/kg, 3 microg/kg or saline solution (placebo). Then, subjects undertake an alcohol cue-reactivity session to assess cue-induced urge to drink, as well as other subjective (e.g. attention to cues) and physiological (heart rate, salivation) measurements of alcohol cue-elicited craving. In this study, administration IV of ghrelin resulted in acute increase in craving (cue-induced urge to drink). Altogether, these data suggest that the ghrelin system may represent a novel pharmacological target to treat patients with alcoholism.

# S27.4 SUBJECTIVE RESPONSES TO ALCOHOL IN THE LAB PREDICT NEURAL RESPONSES TO ALCOHOL CUES {#article-title-5}

Subjective responses to alcohol represent biomarkers of alcoholism liability and treatment response. This study aimed to integrate the human laboratory with neuroimaging by testing whether subjective responses to alcohol during alcohol administration predict neural responses to alcohol cues in the scanner. Study design included a within-subjects controlled alcohol administration in the laboratory followed by an alcohol taste cues blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) task. Twenty alcohol dependent individuals from the Los Angeles community were recruited (6 females; 90% Caucasian; mean age = 29.4). Laboratory assessments of subjective alcohol high, liking, wanting (i.e., craving), positive reinforcement, and negative reinforcement during alcohol administration were entered as predictors of neural response to the presentation of alcohol versus control cues in the scanner (whole-brain cluster-corrected at Z > 1.96, p < 0.05). Alcohol craving during alcohol administration was found to predict less neural activity to alcohol cues in regions including the precentral and postcentral gyri, and supplementary motor area. Alcohol high, however, predicted greater neural activity to alcohol cues in regions including the anterior cingulate cortex, angular gyrus, occipital cortex, and superior parietal lobule. Consistent results were observed across the reinforcement factors such that greater positive and negative reinforcement in the lab predicted greater activation during alcohol cue presentation in regions including the precuneus, anterior cingulate cortex, and cuneal cortex. This study provides initial evidence that subjective responses to alcohol, namely craving, alcohol high, and the reinforcement properties of alcohol, predict neural markers of alcohol cue reactivity. These results also provide support for the validity of both laboratory and neuroimaging measures, and offer an integration of these methods in a sample of alcohol dependent individuals.

# S27.5 COGNITIVE BIAS MODIFICATION (CBM): RETRAINING ADDICTION MEMORY IN ALCOHOL DEPENDENCE {#article-title-6}

The past years we developed and tested several varieties of Cognitive Bias Modification (CBM) aimed at changing the balance between relatively automatic appetitive processes and control processes in addiction (Schoenmakers et al., 2007, Wiers et al., 2010), with promising first applications to alcohol dependent patients (Schoenmakers et al., 2010; Wiers et al., 2011; Eberl et al 2012). We also found across several studies that working memory and other executive control processes moderate the impact of these relatively automatic appetitive processes on behavior (review: Wiers et al. 2013) and that working memory can be successfully trained in problem drinkers (Houben et al 2011). All of these studies have relied on psychological mechanisms only.

Recently, it was reported that applying a low Voltage electrical current over the scalp (transcranial Direct Current Stimulation, tDCS), has the effect that it (temporarily) increases working memory (Fregni et al 2005) and decreases craving (Boggio et al 2008; Fregni et al 2008). We want to investigate whether we can increase the effects of our cognitive training methods by applying tDCS at the same time. I will present results from our first studies.