I. Influence of sex and age on alcohol metabolism and responses Previous research indicates that alcohol metabolism differs between men and women, and may also be influenced by age. There appears to be a complex interaction between sex, age and alcohol elimination rates (AER), and differences in sex steroidal hormones, estrogen and testosterone, may underlie this interaction. Studies have also shown sex- and age-related differences in alcohol PD, although the underlying determinants of these differences are unclear. The objective of this study was to evaluate the influence of sex and age on the PK and PD of IV alcohol in social drinkers. This was a randomized, two-session crossover study in 48 male and female - 24 young (21-25 years) and 24 older (55-65 years) - social drinkers. Subjects underwent the alcohol clamp at target BrACs of 0 and 50mg% for 3 hrs. Results indicated that AERs were significantly higher in males than in females. Age did not appear to influence AER. AER normalized for lean body mass (LBM) was similar between males and females. LBM was significantly associated with AER (r2=0.42) across subjects, indicating that sex differences in AER may be due to sex differences in LBM. There was a significant effect of alcohol on peak subjective perceptions of high, intoxication and drug effects, with no sex differences in responses. Older subjects reported similar peak ratings of high and intoxicated, but significantly lower peak ratings for liking drug effects and wanting more, compared to younger subjects. The effect of alcohol on GH, IGF-1 and sex steroid levels revealed a complex pattern that appeared to differ by sex and age (Vatsalya et al., 2011). Change in free testosterone showed a significant treatment X baseline interaction, indicating that alcohol-induced suppression of testosterone occurred predominantly in men. On the other hand, change in estradiol showed a significant treatment X sex interaction, indicating that alcohol-induced increases in estradiol occurred predominantly in women. There was a trend for alcohol-induced decreases in IGF-1 levels. Change in GH showed a significant main effect of baseline and a trend for treatment by baseline interaction, suggesting an alcohol-induced decrease in individuals with high baseline GH values. There was also a significant main effect of sex indicating that men had greater changes in GH across treatment compared with women. Additional analyses, including PK-PD modeling are being conducted to evaluate the influence of age and sex on subjective responses and heart rate during the alcohol clamp. Findings from these studies will provide a better understanding of age- and sex-related differences in alcohol metabolism, which may underlie medically important differences in individual responses to alcohol. II. Computer-assisted self-infusion of ethanol (CASE) in humans A common feature of almost all addictive drugs is that they are self-administered by both experimental animals and humans. Human alcohol self-administration is generally assessed by measuring the ingestion of alcoholic beverages, typically in a laboratory bar setting. However, these methods tend to be imprecise and may be unreliable due to substantial variability in alcohol exposures, due to differences in the definition of standardized drinks and drinking schedules and due to high inter-individual PK variability. These methods are also subject to various non-pharmacological influences such as alcohol expectancy, beverage preference, choice and monetary value of incentives for drinking. The computer-assisted self-infusion of ethanol method (CASE), using the PBPK-model based infusion algorithm, provides subjects with the flexibility to choose when to push a button to receive alcohol, while providing the investigator with flexibility in controlling the subsequent time course of BrAC (and therefore brain alcohol exposure). This method assures the same increments across all participants and prevents the BrAC from exceeding any pre-set upper limit. Thus, the CASE method focuses on assessment of behavior driven by the pharmacological effects of the drug. The purpose of this study is to characterize the CASE paradigm by assessing ad-lib self-administration behavior (number of button presses), and the resulting BrAC exposure and PD responses in social drinkers. During the CASE session, subjects first undergo a directed priming phase, where they are prompted to push a button to receive standardized alcohol infusions. This is followed by an ad-lib phase, where they have free access to the standardized alcohol infusions. Primary self-administration measures include number of button presses, average BrAC and peak BrAC. Analysis of data from a sample of 52 subjects indicated high test-retest correlations between sessions. Correlations between measures within each session demonstrated a high level of internal consistency. There was a significant association between recent drinking history measures and self-administration measures. There were no sex differences in self-administration measures. A retrospective measure of sensitivity to alcohol (SRE scale) was positively associated with ad lib alcohol self-administration. Sensitivity to positive rewards, measured using the SPSRQ, was also positively associated with ad lib alcohol self-administration. Measures of liking drug effects (measured using DEQ) and urges (measured using AUQ) following the priming phase predicted the number of button presses and average BrAC during the ad lib phase. There was a strong association between peak alcohol effects of feeling drug effects, liking drug effects, intoxication, stimulation and self-administration measures. Data collection for this study is ongoing. More recent efforts have been directed toward developing operant paradigms of human alcohol self-administration, including a progressive ratio (PR) schedule paradigm that requires participants to press the button an increasing number of times for each subsequent alcohol exposure. This paradigm assesses motivation for alcohol reward, and is based on the principle that people will work harder for greater rewards. Outcome measures include the breakpoint, as well as the average and peak BrAC achieved. This method would complement ad lib method in improving the understanding of genetic and environmental determinants of alcohol self-administration. Given the limited data on operant alcohol self-administration in humans, initial studies are focused on evaluating test-retest reliability and the effect of recent drinking history on operant alcohol self-administration. The Section is also conducting studies using the CASE method to examine the effects of pharmacological agents on the rate, magnitude and pattern of exposure to alcohol in heavy drinkers. Such a paradigm would serve as a biomarker of clinical efficacy in the early stages of development of drugs for the treatment of alcohol-dependence. The first of these studies is ongoing. This randomized, double-blind placebo-controlled study aims to evaluate the effect of varenicline on alcohol self-administration using the CASE method in non-treatment seeking heavy drinkers. III. Additional Studies: 1) Effect of alcohol on fMRI BOLD response in healthy social and heavy drinkers (Daniel Hommer, P.I.). Study has been completed and paper is in press (Gilman et al., 2011a). 2) Effect of alcohol on neural correlates of risky decision-making in healthy social drinkers (Daniel Hommer, P.I.). Study has been completed and paper is in press (Gilman et al., 2011b). 3) Effect of naltrexone on the BOLD signal in the ventral striatum during the alcohol clamp in alcohol-dependent individuals (David T. George, PI). Data collection has been completed, and analysis is ongoing.