The clinical PK of alcohol have been the evaluated extensively. Studies have emphasized the high (3-4 fold) inter- and intra-individual variation in alcohol PK, which may be due to drinking history, food effects, sex, age, body weight/composition, and genetic polymorphisms of the alcohol metabolizing enzymes ADH and ALDH. The PD effects of alcohol have also been well-studied, and a variety of behavioral and physiological measures have been used to examine the genetic and environmental determinants of variability in alcohol PD. In order to characterize the PD effects, it is critical to control the PK variability and the resulting systemic alcohol exposure that drives the pharmacological effects of alcohol.? ? The alcohol clamp is a method that uses an IV alcohol infusion to achieve and maintain a pre-determined target (+/- 5%) breath alcohol concentration (BrAC) for a prescribed duration. The infusion rate is based on a physiologically-based PK (PBPK) model for alcohol and is computed using individualized model parameter estimates. During the alcohol clamp, the steady-state alcohol infusion rate is a measure of the alcohol elimination rate (AER). Thus, the alcohol clamp provides a unique platform for evaluating the genetic and environmental determinants of the PK and PD of alcohol in humans. ? ? 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 elderly are thought to be more sensitive to alcohol than younger groups; however, it is not clear if these changes are due to PK or PD differences. ? ? 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. ? ? Preliminary analyses have been conducted to evaluate sex differences in AER in the younger group and age-related differences in AER in males (only 8/12 older females have completed the study so far). AERs were found to be significantly higher in males than in females in the younger age group, as expected. AER normalized for lean body mass was similar between males and females, indicating that sex differences in AER may be accounted for, in part, by lean body mass. Age did not appear to influence AER in males. Lean body mass explained approximately 53% of the variance in AER across females and young and older males. Future plans include completion of data collection and analyses to examine age effects in females as well as sex effects in the older subjects. Additional analysis will evaluate the role of liver volume and sex steroid levels on AER. PK-PD modeling will be conducted to evaluate the influence of age and sex on subjective perception and heart rate changes during the alcohol clamp.? ? This study will provide 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. Changes in self-administration in humans 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 alcohol self-administration in humans 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 (time course of BrAC) due to differences in the definition of standardized drinks and drinking schedules as well as the 3 to 4-fold inter-individual PK variability. Additionally, alcohol exposure cannot be controlled once ingestion has taken place, and these methods are subject to various non-pharmacological influences such as individual differences in alcohol expectancy, beverage preference, choice and monetary value of incentives (or disincentives) for drinking, etc.? The alcohol clamp substantially reduces the 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. ? ? 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-Rac 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.
