The investigators hypothesize that varenicline will dose dependently attenuate the subjective effects of cigarettes after a period of abstinence. Also, treatment with varenicline will dose dependently weaken the severity of nicotine withdrawal symptoms. Thirdly, we hypothesize that treatment with varenicline will dose dependently decrease cigarette self-administration in the model proposed.

Tobacco use is the leading preventable cause of death in the U.S.A. Every year 400,000 people die from cigarette smoking and in 2006, one out of every five deaths in the US were smoking related. Recent advances in laboratory studies of tobacco effects in humans and in understanding the effects of nicotine on the brain and behavior present an opportunity to advance medication development.

The addictive properties of nicotine are thought to be a result of nicotine triggering the acute release of dopamine, a pleasurable event that a person seeks to repeat. Varenicline is a partial agonist of the nicotine receptors, therefore also triggering the release of dopamine but in a more sustained and moderate manner, which could counter the low dopamine levels arising from a lack of nicotine and therefore aid craving. Also, by binding to these nicotine receptors in advance of smoking, it could stop nicotine from binding and creating pleasurable effects.

This study will assess the effect of acute treatment with varenicline and placebo on early tobacco withdrawal, acute effects of cigarettes and cigarette self-administration in cigarette-smoking volunteers. After overnight abstinence, participants will come into the lab and receive acute treatment with varying doses of varenicline or placebo and perform computer tests and fill out questionnaires. Then they will be given the opportunity to smoke under operational conditions (cigarette versus money choice). This study will employ a within-group, double-blind, randomized and counterbalanced design.

The main goal of this project is to improve the current laboratory model of smoking cessation and study the mechanism involved in smoking maintenance. We hypothesize that varenicline will dose-dependently: 1) decrease nicotine withdrawal symptoms, 2) decrease acute effects of cigarettes and 3) decrease self-administration of cigarettes in the laboratory paradigm. Showing the effectiveness of varenicline in the proposed laboratory model will confirm the model's predictive validity to detect clinically effective medication.

Inclusion Criteria:

1. A diagnosis of nicotine dependence with physiological dependence, smoking at least 15 cigarettes/day during the last 3 months.
2. Not interested in treatment
3. Medically healthy on the basis of physical examination and medical history, vital signs, EKG and laboratory tests, with a negative pregnancy test for females.
4. Able to perform study procedures
5. Males or females between the ages of 21-45 yrs
6. Female participants agree to use an effective method of birth control during the course of the study

Exclusion Criteria:

1. A diagnosis of abuse or dependence on alcohol or drugs other than nicotine
2. Current Axis I diagnosis or current treatment with psychotropic medications (within last 3 months)
3. Lifetime history of schizophrenia or other psychotic disorders, bipolar disorder, or anxiety disorders
4. Currently seeking treatment for nicotine dependence
5. Participants on parole or probation
6. History of significant recent violent behavior
7. Blood pressure > 150/90
8. History of allergic reaction to any of the study medications

Adverse events reported during 4 experimental sessions