Nicotine acts on nicotinic cholinergic receptors, triggering the release of neurotransmitters that produce psychoactive effects that are rewarding. With repeated exposure, tolerance develops to many of the effects of nicotine, thereby reducing its primary reinforcing effects and inducing physical dependence (i.e., withdrawal symptoms in the absence of nicotine). Smoking behavior is influenced by pharmacologic feedback and by environmental factors such as smoking cues, friends who smoke, stress, and product advertising. Levels of nicotine in the body in relation to a particular level of nicotine intake from smoking are modulated by the rate of nicotine metabolism, which occurs in the liver largely by means of the enzyme CYP2A6. Other factors that influence smoking behavior include age, sex, genetics, mental illness, and substance abuse.

Nicotine activates α₄β₂^* receptors in the ventral tegmental area, resulting in dopamine release in the shell of the nucleus accumbens.

Craving — induced by smoking cues, stressors, or a desire to relieve withdrawal symptoms — triggers the act of smoking a cigarette, which delivers a spike of nicotine to the brain. Nicotinic cholinergic receptors (nAChRs) are activated, resulting in the release of dopamine and other neurotransmitters, which in turn cause pleasure, stimulation, and mood modulation. Receptor activation also results in the development of new neural circuits (neural plasticity) and, in association with environmental cues, behavioral conditioning. After being activated by nicotine, nAChRs ultimately become desensitized to it, which results in short-term tolerance of nicotine and reduced satisfaction from smoking. In the time between smoking cigarettes, or after quitting tobacco use, brain nicotine levels decline, which leads to reduced levels of dopamine and other neurotransmitters and to withdrawal symptoms, including craving. In the absence of nicotine, nAChRs regain their sensitivity to nicotine and become reactivated in response to a new dose. Adapted from Dani and Heinemann.35

The first cigarette of the day has a substantial pharmacologic effect, primarily arousal, but at the same time, tolerance to nicotine begins to develop. A second cigarette is smoked later, at a time when the smoker has learned that there is some regression of tolerance. With subsequent smoking, there is an accumulation of nicotine in the body, resulting in a greater level of tolerance, and withdrawal symptoms become more pronounced between successive cigarettes. The shaded area of the graph represents the affective neutral zone that exists between the threshold level of nicotine needed to produce pleasure and arousal and the threshold level below which withdrawal symptoms will occur. Transiently high levels of nicotine in the brain after individual cigarettes are smoked may partially overcome tolerance, but the primary (euphoric) effects of nicotine tend to lessen throughout the day. Abstinence overnight allows considerable resensitization to the actions of nicotine. Adapted from Benowitz.47