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Nicotine Dependence Begins with the First Cigarette Joseph R. DiFranza, M.D. University of Massachusetts Medical School Robert J. Wellman, Ph.D. Fitchburg State College Traditional Model of Nicotine Dependence • Nicotine is rewarding Traditional Model of Nicotine Dependence • Nicotine is rewarding • Reward drives heavier tobacco use Traditional Model of Nicotine Dependence • Nicotine is rewarding • Reward drives heavier tobacco use • Tolerance builds up over two or more years of continual smoking Traditional Model of Nicotine Dependence • Nicotine is rewarding • Reward drives heavier tobacco use • Tolerance builds up over two or more years of continual smoking • Tolerance causes dependence and withdrawal symptoms The DANDY Study • Symptoms of dependence occur after the first few cigarettes The DANDY Study • Symptoms of dependence occur after the first few cigarettes • Many novice smokers experience withdrawal symptoms while smoking only occasionally, although it may take days between cigarettes for symptoms to appear The DANDY Study • Symptoms of dependence occur after the first few cigarettes • Many novice smokers experience withdrawal symptoms while smoking only occasionally, although it may take days between cigarettes for symptoms to appear • Craving for a cigarette is the most common first symptom experienced by novice smokers Implications of the DANDY Findings • Withdrawal symptoms occur before tolerance to nicotine has developed Implications of the DANDY Findings • Withdrawal symptoms occur before tolerance to nicotine has developed • Tolerance and withdrawal are caused by different physiological mechanisms Implications of the DANDY Findings • Withdrawal symptoms occur before tolerance to nicotine has developed • Tolerance and withdrawal are caused by different physiological mechanisms • The effects of a single cigarette last for days Sensitization • Occurs when subsequent doses of a drug produce a greater response Sensitization • Occurs when subsequent doses of a drug produce a greater response • Develops after only a few doses of most addictive drugs, including nicotine Sensitization • Occurs when subsequent doses of a drug produce a greater response • Develops after only a few doses of most addictive drugs, including nicotine • In animals, is expressed as an increase in locomotor activity (behavioral sensitization) Sensitization • Occurs when subsequent doses of a drug produce a greater response • Develops after only a few doses of most addictive drugs, including nicotine • In animals, is expressed as an increase in locomotor activity (behavioral sensitization) • Expression is blocked when dosing is too frequent Expression of Sensitization is Blocked When Dosing is Too Frequent Reprinted with permission from Shuster, L., Webster G. W., & Yu, G. (1975). Perinatal narcotic addiction in mice: Sensitization to morphine stimulation. Addictive Diseases, 2, 277-292. Receptor in Baseline State Acetylcholine Receptor Activated First Dose of Nicotine Nicotine Receptor Activated Nicotine Receptor Deactivated Receptor Up-regulation Intermittent Smoking Nicotine Daily Smoking Nicotine The Sensitization-Homeostasis Model The Craving Generation System CGS Craving The Sensitization-Homeostasis Model The Craving Inhibition System CIS CGS Craving The Sensitization-Homeostasis Model Acetylcholine (Stimulatory) CIS CGS Craving The Sensitization-Homeostasis Model Acetylcholine (Stimulatory) CIS Dopamine (Inhibitory) CGS Craving The Sensitization-Homeostasis Model Acetylcholine (Stimulatory) CIS Dopamine (Inhibitory) CGS Craving With intermittent smoking, nicotine acts on up-regulated receptors and produces a sensitized response. Nicotine CIS CGS The sensitized response produces super-physiologic inhibition of the CGS Nicotine Sensitized Response CIS CGS Super-physiologic inhibition of the CGS provokes homeostatic adaptations which increase activity in the CGS Nicotine CIS ++ CGS ++ Homeostatic Adaptations The homeostatic adaptations cause the CGS to become autonomous, producing craving when it is not inhibited. CIS ++ CGS ++ The Loss of Autonomy Craving What causes nicotine withdrawal? Withdrawal: Unopposed Homeostatic Adaptations ++ ++ Irritability ++ CGS ++ Difficulty Concentrating Craving If youths have nicotine withdrawal symptoms… how can they go days between cigarettes? Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors. Acetylcholine CIS Up-regulated Receptors ++ CGS ++ Craving Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors. Acetylcholine CIS Up-regulated Receptors ++ CGS ++ Craving Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors. Acetylcholine CIS Up-regulated Receptors ++ CGS ++ Craving If addicted smokers can get by with a cigarette every few days… why do people have to smoke more as time goes by? Acetylcholine inhibits the CGS between cigarettes. Acetylcholine CIS ++ CGS ++ Repeated inhibition provokes more permanent homeostatic adaptations to stimulate the CGS. Tolerance Acetylcholine CIS ++ CGS ++ With this additional stimulation to the CGS, acetylcholine is no longer sufficient to inhibit craving between cigarettes. Tolerance Acetylcholine CIS ++ CGS ++ Craving Nicotine The smoker begins to smoke more frequently to suppress craving. Tolerance CIS ++ CGS ++ Craving When cigarettes are spaced a day apart, a sensitized response is obtained... Tolerance Nicotine ++ CIS CGS Sensitized Response to Nicotine ++ Craving …and craving is temporarily blocked. Tolerance Nicotine CIS ++ CGS ++ Craving Tolerance strengthens slowly over time, prompting more frequent smoking. Nicotine CIS Tolerance ++ CGS ++ Craving When use exceeds one cigarette per day, receptors are deactivated and a sensitized response cannot be elicited. Tolerance Nicotine CIS ++ CGS ++ Craving With deactivated receptors, acetylcholine is of no help in suppressing craving between cigarettes. Tolerance Acetylcholine CIS ++ CGS ++ Craving With heavy smoking, craving is suppressed when nicotine is present in high concentration. Tolerance Nicotine CIS ++ CGS ++ Craving Craving returns quickly when nicotine levels fall. Tolerance CIS ++ CGS ++ Craving What happens with cessation? Within 24 hours receptors become reactivated, but acetylcholine is too weak to inhibit craving after tolerance has developed. Tolerance Acetylcholine CIS ++ CGS ++ Craving is intense The homeostatic adaptations within the CGS begin to fade immediately. Tolerance Acetylcholine CIS + CGS Craving becomes less intense Within a month, receptors have down-regulated, restoring inhibition of the CGS to non-smoker levels. Tolerance Acetylcholine CIS CGS Craving Stimulation from tolerance continues to produce craving. Homeostatic adaptations develop to oppose the constant stimulation provided by tolerance. Tolerance Acetylcholine CIS ++ CGS ++ The CGS is in balance. Craving is blocked. Craving Why does a single cigarette cause a relapse? A single dose of nicotine causes a sensitized response. Tolerance Nicotine CIS ++ CGS ++ Craving A single dose of nicotine causes a sensitized response. Tolerance Nicotine CIS ++ CGS ++ Craving The resulting super-physiologic inhibition of the CGS causes the inhibitory homeostatic adaptations to disappear. Tolerance CIS CGS Craving Tolerance causes an immediate resumption of strong craving. Tolerance CIS CGS Craving Nicotine Dependence Begins with the First Cigarette Funded by The National Institute on Drug Abuse
