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Neurotransmitter systems and tobacco smoking

Institution: University of California, Los Angeles
Investigator(s): Richard Olmstead, Ph.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8RT-0078H Award: $430,910
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
The prevalence of smoking has decreased dramatically over the last fifty years in the United States, and especially in California where approximately only 18% of the population smokes. The negative health consequences of smoking are well known and even most current smokersindicate some desire to quit. Nonetheless, this year more than 4 million Californians will continue to smoke and hundreds of thousands will start smoking. Clearly there must be strong reasons why such a large number of people are willing to endanger their health. Social and psychological explanations partially explain this behavior. However, another area which has received increasing interest is the study of the neurochemical basis for smoking. Neurochemicals (specifically neurotransmitters) are substances that control the functioning of neurons (nerve cells) in the body and brain and hence thinking and feeling.

Although much progress has been made on increasing understanding of the connection between smoking and neurotransmitters, there remain many unanswered questions. This is in part due to the fact that A) neurotransmitter action cannot be directly observed in living humans and B) nicotine, the primary addictive substance in tobacco, has widespread effects in the brain on a large number of different neurotransmitters. When tobacco is smoked, nicotine reaches the brain in approximately ten seconds and substitutes for the naturally occurring neurotransmitter. Experiment 1 will test a new drug, M100907; the second experiment will test naltrexone; and the third experiment will test divalproex sodium.

In the basic research paradigm, subjects are observed over 6 or 12 hours during which time their smoking behavior (number of puffs, length of puffs, carbon monoxide and nicotine intake, verbal desire to smoke, etc.) as well as their general mood is carefully recorded. This procedure will be done on three days at least week apart which will differ by whether the participant receives a zero, low or high dose of the drug under study. Changes in smoking behavior across different dose conditions will be assessed. It is expected that there will be differences in smoking behavior across dose levels for each study drug, however, the direction of these differences (positive or negative) will vary across drugs depending on the neurotransmitter system involved. In each experiment we will study regular ("a pack a day") smokers. Within Experiment 2, however, we will also test "chippers" (i.e., those who smoke fewer than 5 cigarettes a day and who are apparently not nicotine dependent). In this case, we predict that naltrexone may have a proportionally greater effect on chippers who may be smoking more for pleasurable effects unlike regular smokers who more likely smoke for withdrawal relief.

It is expected that this work will shed light on the neurochemical basis of smoking and nicotine addiction and will likely provide direction toward new treatments for smoking and tobacco cessation. The study of non-dependent smokers will result in a greater understanding of ways which dependence may develop and inform us as to possible interventions.
Publications

The acute effects of low dose naltrexone in normal heavy smokers.
Periodical: Society for Research on Nicotine and Tobacco Conference Index Medicus:
Authors: Caskey NH, Olmstead RE, Jarvik ME, Madsen DC, Iwamoto-Schaap PN, et al. ABS
Yr: 2001 Vol: 7 Nbr: Abs: Pg:

The acute effects of low dose naltrexone on ad lib smoking in normal heavy smokers and chippers.
Periodical: TRDRP Annual Report to the State of California Legislature Index Medicus:
Authors: Olmstead RE, Caskey NH, Madsen DC, Terrace SM, et al. ABS
Yr: 2001 Vol: Nbr: Abs: Pg:

The acute effects of low dose depakote on ad lib smoking in normal and heavy smokers.
Periodical: Society for Research on Nicotine and Tobacco Conference Index Medicus:
Authors: Olmstead RE, Caskey NH, Madsen DC, Terrace SM, et al. ABS
Yr: 2002 Vol: Nbr: Abs: Pg: