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Neuroendocrine responses to nicotine: a physiologic probe

Institution: University of California, San Francisco
Investigator(s): Lori Karan, M.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7KT-0031 Award: $225,000
Subject Area: Nicotine Dependence
Award Type: New Investigator Awards

Initial Award Abstract
The objective of this research is to describe the magnitude and time course of changes in the body's hormone levels which occur in response to single and multiple doses of nicotine. Nicotine's addictive and mood altering properties are in a large part. due to its effects on hormones, which play a key role in the body's state of arousal and alertness, attention, anxiety and response to stress. When released, hormones not only have effects in target organs but they also provide feedback, adjusting the body's future receptivity to nicotine's further action upon the body. Quantitative measures of this response can form the basis for understanding why persons differ from each other in being susceptible to nicotine addiction. It can also explain why people smoke with various intensities, and differ in their ability to quit cigarettes.

Surprisingly, the careful work required to develop reliable. quantitative methods for studying nicotine's hormonal response in human subjects has not yet been done. The research proposed will require three years, and it is separated into six studies which will provide increasingly specific information. This sequencing of the research will allow us to use early results in our own later studies and to publish these result so they can be used more quickly in others' research as well.

The first two studies focus upon current smokers. The first study is designed to determine which hormones, among a large number of possible ones, are responsive to a dose of nicotine and to determine the optimum nicotine dose to elicit this response. The second study is designed to demonstrate the reproducibility of an individual's response and compare this response with that of placebo and with that of smoking two cigarettes.

The third and fourth studies will repeat the measurements for volunteer subjects who have never smoked and for those who have smoked but quit. The magnitude and time course of the hormone responses will be compared for current smokers, ex smokers, and never smokers. These data are fundamentally significant; hypotheses will be generated to explain any differences that are seen.

The fifth study will develop quantitative relationships between the response levels of hormones in samples of arterial and venous blood. Although it would be scientifically more accurate to only test samples of blood before the blood circulates throughout the body, collecting arterial blood is too invasive to carry out routinely. A model to compute arterial levels from venous levels will be developed to enable use of venous sampling in future, larger studies.

The sixth and final study of this series will demonstrate the use of these techniques in . quantitative investigation of smokers' tolerance to nicotine, the decreased response to nicotine which occurs as nicotine's dose or frequency of administration increases.. This study will be done by monitoring the subjects' hormone responses to a sequence of two injections of nicotine, at various timed intervals. These data will enable better understanding of how the body responds to repeated doses of nicotine.

Although these investigations will produce fundamentally significant new knowledge, their primary motivation is to prototype a well defined, reliable and affordable methodology. This methodology can be used for research on diverse populations, and across genetic and environmental factors. Having a quantitative probe to study nicotine's actions upon the body's central nervous system will stimulate important research to further prevent, diagnose and treat tobacco related diseases.