1) 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 metabolism, 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 is to evaluate the influence of sex and age on the metabolism and acute response to alcohol in social drinkers. This is a randomized, two-session crossover study in 48 male and female - 24 young (21-25 years) and 24 older (55-65 years) - social drinkers. Participants will undergo the alcohol clamp at target BrACs of 0 and 50 mg% for 3 hrs. The AER and behavioral and physiological responses to alcohol will be evaluated. Enrollment for this study is now complete. Preliminary analysis indicates that AERs are significantly higher in males than in females, as expected. AER/LBM was similar between males and females, indicating that sex differences in LBM may contribute to the observed sex differences in AER. Age did not appear to influence AER. AER/LBM was higher in older compared to younger subjects. LBM was significantly associated with AER (r2=0.42) across subjects. LV was also significantly associated with AER (r2=0.23) across subjects. Analysis of the PD data showed a significant effect of alcohol on peak subjective perceptions of high, intoxication and drug effects. There were no sex differences in subjective responses to clamped BrACs. Older subjects reported similar peak ratings of high and intoxicated as younger subjects. However, they showed significantly lower peak ratings for liking drug effects and wanting more than younger subjects. These results are being written up for publication. Analysis is ongoing to evaluate the role of sex steroid levels on AER as well as the effect of alcohol on sex steroid levels. PK-PD modeling will be conducted to evaluate the influence of age and sex on subjective and heart rate changes during the alcohol clamp. This study is providing valuable information about the effects of age and sex on alcohol metabolism and response. Findings from these studies will provide a better understanding of age- and sex-related differences in metabolic processes, which may underlie medically important differences in individual responses to alcohol. 2) Computer-assisted self-infusion of ethanol (CASE) in humans Self-administration is a well-established characteristic of addictive drugs. The extensive literature on alcohol self-administration in animal models has clearly demonstrated the power of this method in documenting genetic influences on the development of alcoholism, as well as to assess the ability of pharmacological agents to reduce alcohol consumption as a screen for pharmacotherapy of alcohol dependence. A change in human alcohol self-administration has also been established as a measure of the effectiveness of drugs that have been approved for the pharmacological treatment of alcohol dependence. The usual method of studying human alcohol self-administration is by assessing the ingestion of alcoholic beverages, typically in a laboratory setting. However, these methods remain imprecise and may be unreliable because they are subject to substantial variability in alcohol exposures due to differences in the definition of standardized drinks and drinking schedules as well as the high inter-individual PK variability. Also, alcohol exposure cannot be controlled once alcohol is ingested, and these methods are subject to various non-pharmacological influences such as alcohol expectancy, beverage preference, choice and monetary value of incentives (or disincentives) for drinking, etc. The alcohol clamp minimizes variability in BrAC following alcohol administration and provides exquisite control of the time course of BrAC. A computer-assisted method of alcohol self-administration, using the PBPK-model based infusion algorithm, would provide subjects flexibility in choosing when to push a button to receive alcohol, while providing the investigator with flexibility in controlling the subsequent time course of breath (and therefore brain) alcohol exposure, assuring the same increments across all participants, and preventing the BrAC from exceeding any pre-set upper limit. The increments in BrAC following each button-push can be specified as a fixed dose, a fixed incremental increase in BrAC or a fixed ascending and descending rate of change of BrAC. With this method, the subject will have direct control over the initiation of incremental exposures, but only indirect control over the alcohol infusion. The goal of this project is to characterize the computer-assisted self-infusion of ethanol (CASE) paradigm by assessing self-administration behavior and the resulting BrAC exposure and PD responses in healthy social drinkers. The study will also evaluate the test-retest reliability of CASE and examine the influence of sex and recent drinking history on CASE measures. During the CASE session, subjects will first undergo a directed priming phase, where they will be prompted to push a button to receive standardized alcohol infusions. This will be followed by an ad-lib phase, where they will have free access to the standardized alcohol infusions. BrAC will be measured, and physiological and subjective measures of alcohol effects and urges will be assessed. Data collection for this study is ongoing. Preliminary analysis of the first group of subjects suggests high test-retest reliability of the CASE method. The primary measures, average BrAC achieved and number of alcohol requests during the ad lib self-administration phase, had correlation coefficients of 0.91 and 0.92 respectively. Additional Studies / Future Directions: Three additional studies, employing the alcohol clamp method, are underway: 1) Effect of alcohol on BOLD response to emotional visual stimuli using fMRI in healthy social and heavy drinkers (Daniel Hommer, PI). 2) Effect of mu-opioid receptor gene (A118G) polymorphism on the response to alcohol, including dopamine release (using 11C-Raclopride displacement), in healthy social drinkers (Markus Heilig, PI). 3) Effect of naltrexone on the BOLD signal in the ventral striatum during the alcohol clamp in alcohol-dependent individuals (David T. George, PI). The Unit is also developing 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 could 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 was initiated earlier this year. 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.

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