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Tobacco use remains at epidemic levels in the U.S, with 20% of adults being smokers. Most smokers start as adolescents, and almost all current smokers have tried their first cigarette by age 18. Although 40% of smokers have attempted to quit at least once within the last year, the vast majority fail. While there are several drug therapies available to help people quit, including the nicotine patch and two prescription medications (bupropion and varenicline), only about 25% of people who use these treatments remain smoke-free for a full year.
The gold standard preclinical model to evaluate treatments for smoking cessation is an animal test of nicotine self-administration. In this test, an animal learns to press a lever or to poke its nose in a hole in a test box in order to receive an intravenous infusion of nicotine. Although varenicline, the newest drug for smoking cessation, can reduce the amount of nicotine an animal will self-administer, this test is not an accurate model of smoking. Whereas nicotine is considered to be the primary addictive component of tobacco smoke, there is now growing evidence to suggest that other compounds in the smoke may also play a role. Furthermore, adolescent brains are less mature than that of adults and may respond differently to drugs. Yet, adult animals have been used almost exclusively in preclinical testing. We believe that the poor success rate of drug treatments for smoking cessation may result from the failure of the primary experimental model to account for the influence of non-nicotine chemicals in tobacco smoke, and a lack of attention to possible effects of age.
To address these shortcomings, we propose to test the behavioral and neural activating effects of an aqueous cigarette smoke extract (CSE), a solution made by bubbling tobacco smoke through water. This extract contains nicotine along with many other chemicals, all at approximately the same concentrations that a smoker would inhale. In preliminary self-administration studies, we have shown that adult rats are sensitive to lower doses of CSE than equivalent doses of nicotine alone. We will now compare the effects of CSE in adult and adolescent rats, and will test the hypothesis that adolescents are more sensitive to the rewarding effects of CSE. In addition, because many smokers may use tobacco to help treat symptoms of depression or anxiety, we will test whether CSE more potently relieves these symptoms than nicotine alone.
We also aim to understand how CSE produces its behavioral effects and whether these mechanisms are different in adolescents and adults. To do so, we will measure patterns of brain activation induced by CSE and nicotine by analyzing regional expression of a gene that is ‘turned on’ by neuronal activation. We will also test the effect of drugs on monoamine oxidase, an enzyme that breaks down neurotransmitters such as dopamine and serotonin. The activity of this enzyme is greatly reduced in smokers, but is unaffected by pure nicotine. We hypothesize that non-nicotine constituents in CSE will block monoamine oxidase activity in rat brain.
These studies have the potential to create a powerful new model to test smoking cessation treatments. Using CSE rather than pure nicotine should help to create more effective treatments for humans by modeling all of the actions of tobacco smoke, rather than just those of nicotine. Our research will also determine whether there are age differences in response to tobacco constituents and may even reveal ways in which we can differentially treat smokers of different ages for better cessation outcomes. |
