Administration of alcohol to human and animals is an integral part of research targeted to the understanding of the brain's response to alcohol, the genetic and environmental factors that influence those responses, and to the development of pharmaceuticals for the treatment of alcohol dependence. The IARC has developed methods for the precise prescription of the time course of brain exposure to alcohol and for measuring the time course of self-administered alcohol.
In laboratory studies of the response to alcohol, the primary problem is the inability to control the time course of absorption and first pass metabolism of ingested alcohol. Using a physiologically-based pharmacokinetic (PBPK) model of alcohol distribution and elimination, it is possible to overcome the kinetic variability among individuals in order to study the sources of pharmacodynamic variability in the sample population. The graph on the left, below, shows the time courses of breath alcohol concentration following ingestion of a dose of alcohol that was calculated and administered with every possible effort to minimize the variation in brain exposure across individuals. The graph on the right shows the adherence to a prescribed “clamped” time course using PBPK model-driven intravenous infusion of 6% ethanol.
|Ramchandani VA, O'Connor S, Neumark Y, Zimmermann US, Morzorati SL, de Wit H: (2006) The alcohol clamp: applications, challenges, and new directions Alcohol Clin Exp Res. 30(1):155-64|
Laboratory studies of alcohol self-administration are used for evaluating the influence of several factors (e.g. age, genes, pharmaceutical interventions) on wanting and liking of ethanol. By incorporating the PBPK model in a subject-driven shell, the Computer-assisted Self-administration of Ethanol system (CASE) achieves several advantages over oral self-administration methods.
CASE provides precisely the same incremental time course of brain exposure in all subjects following the election of another "drink." There is no confusion of the brain's response to alcohol, per se, with expectations created by the taste or odor of a drink. The CASE system will not permit any subject's exposure to exceed a preset limit. The CASE system can implement any incremental exposure in any paradigm the investigator chooses.
Zimmermann U, Mick I, Vitvitskyi V, Plawecki, M, Mann K, O’Connor S: Development and pilot validation of Computer-Assisted Self-infusion of Ethanol (CASE): a new method to study alcohol self-administration in humans. Alcohol Clin Exp Res
The tools for alcohol clamping and CASE systems have been automated, validated and published. These tools, and the hands-on education needed to employ them in laboratory research are available to the field, and can be tailored to specific applications by writing to Sean O'Connor.