As would be expected with substances associated with tolerance and addictive properties, neuroadaptation occurs with chronic nicotine exposure. A suspected biological correlate of this is an increase in nAChRs in the brain. This increase is thought to reflect nicotine-mediated desenstitization, meaning that more nicotine is required to deliver the same neurochemical effect. For example, nicotine withdrawal in rodent models is associated with increased threshold for intracranial self-stimulation, indicating reduced reward due to inadequate dopamine release. Independent of nicotine effects, cigarette smoking is associated with decreased activity of monoamine oxidase enzymes in the brain, which are associated with the degradation of dopamine. Inhibition of monoamine oxidase activity would augment nicotine effects of increasing dopamine levels and contribute to positive reinforcement, tolerance, and addiction.
As most smokers report, stopping smoking is acutely associated with withdrawal symptoms of irritability, restlessness, anxiety, problems getting along with friends and family, difficulties concentrating, increased hunger and eating, and cravings for tobacco. Another symptom is the lack of pleasure or enjoyment, known as anhedonia. These symptoms are believed to be due to the relative deficiency in dopamine release, related to nicotine-mediated changes in receptor function and structure. Nicotine addiction is thus sustained by a combination of positive effects of nicotine on neurotransmitter levels related to pleasure and arousal, the dampening effect of those pleasure or reward mechanisms over time, and the need for continued nicotine exposure to avoid the negative affects related to the decreased neurotransmitter levels, particularly that of dopamine, that would occur without nicotine. However, in addition to the pharmacological mechanisms of nicotine, conditioning is also thought to play an important role in tobacco addiction.
With regular drug use, specific moods or other environmental factors, known as “cues,” become associated with the pleasurable or rewarding effects of the drug. This association between the cues and the anticipated pleasure associated with the drug, known as conditioning, is a powerful contributor to addiction (O’Brien 2001). Smoking is maintained in part by conditioning. For example, smoking becomes associated with specific behaviors, such as drinking a cup of coffee or alcohol. Repetition of these coexisting behaviors over time leads to the behavior becoming a cue the person to want to smoke. Behaviors can be conditioned to either the positive or negative reinforcing effects of nicotine. For example, because smoking becomes associated with relieving the negative affects of nicotine withdrawal, the smoker can associate smoking with relieving other negative feelings, such as stress. Managing conditioned behaviors is often an important factor in the success of nicotine cessation.