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Nicotine Dependence Begins with the First Cigarette

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.

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Nicotine Dependence Begins with the First Cigarette

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  1. 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

  2. Traditional Model of Nicotine Dependence • Nicotine is rewarding

  3. Traditional Model of Nicotine Dependence • Nicotine is rewarding • Reward drives heavier tobacco use

  4. Traditional Model of Nicotine Dependence • Nicotine is rewarding • Reward drives heavier tobacco use • Tolerance builds up over two or more years of continual smoking

  5. 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

  6. The DANDY Study • Symptoms of dependence occur after the first few cigarettes

  7. 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

  8. 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

  9. Implications of the DANDY Findings • Withdrawal symptoms occur before tolerance to nicotine has developed

  10. Implications of the DANDY Findings • Withdrawal symptoms occur before tolerance to nicotine has developed • Tolerance and withdrawal are caused by different physiological mechanisms

  11. 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

  12. Sensitization • Occurs when subsequent doses of a drug produce a greater response

  13. Sensitization • Occurs when subsequent doses of a drug produce a greater response • Develops after only a few doses of most addictive drugs, including nicotine

  14. 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)

  15. 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

  16. 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.

  17. Receptor in Baseline State Acetylcholine Receptor Activated

  18. First Dose of Nicotine Nicotine Nicotine Receptor Deactivated Receptor Activated

  19. Receptor Up-regulation

  20. Intermittent Smoking Nicotine

  21. Daily Smoking Nicotine

  22. The Sensitization-Homeostasis Model CGS The Craving Generation System Craving

  23. The Sensitization-Homeostasis Model CIS CGS The Craving Inhibition System Craving

  24. The Sensitization-Homeostasis Model CIS CGS Acetylcholine (Stimulatory) Craving

  25. The Sensitization-Homeostasis Model CIS CGS Acetylcholine (Stimulatory) Dopamine (Inhibitory) Craving

  26. The Sensitization-Homeostasis Model CIS CGS Acetylcholine (Stimulatory) Dopamine (Inhibitory) Craving

  27. With intermittent smoking, nicotine acts on up-regulated receptors and produces a sensitized response. CIS CGS CGS Nicotine

  28. The sensitized response produces super-physiologic inhibition of the CGS CIS Sensitized Response CGS Nicotine

  29. Super-physiologic inhibition of the CGS provokes homeostatic adaptations which increase activity in the CGS CIS CGS + + Nicotine + + Homeostatic Adaptations

  30. The homeostatic adaptations cause the CGS to become autonomous, producing craving when it is not inhibited. CIS CGS + + Craving + + The Loss of Autonomy

  31. What causes nicotine withdrawal?

  32. Withdrawal:Unopposed Homeostatic Adaptations CGS + + + + Irritability + + Craving + + Difficulty Concentrating

  33. If youths have nicotine withdrawal symptoms… how can they go days between cigarettes?

  34. Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors. Acetylcholine CIS CGS + + + + Craving Up-regulated Receptors

  35. Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors. Acetylcholine CIS CGS + + + + Craving Up-regulated Receptors

  36. Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors. Acetylcholine CIS CGS + + + + Craving Up-regulated Receptors

  37. If addicted smokers can get by with a cigarette every few days… why do people have to smoke more as time goes by?

  38. Acetylcholine inhibits the CGS between cigarettes. Acetylcholine CIS CGS + + + +

  39. Repeated inhibition provokes more permanent homeostatic adaptations to stimulate the CGS. Tolerance Acetylcholine CIS CGS + + + +

  40. With this additional stimulation to the CGS, acetylcholine is no longer sufficient to inhibit craving between cigarettes. Tolerance Acetylcholine CIS CGS + + + + Craving

  41. The smoker begins to smoke more frequently to suppress craving. Tolerance Nicotine CIS CGS + + + + Craving

  42. When cigarettes are spaced a day apart, a sensitized response is obtained... Tolerance Nicotine CIS CGS + + + + Craving Sensitized Response to Nicotine

  43. …and craving is temporarily blocked. Tolerance Nicotine CIS CGS + + + + Craving

  44. Tolerance strengthens slowly over time, prompting more frequent smoking. Tolerance Nicotine CIS CGS + + + + Craving

  45. When use exceeds one cigarette per day, receptors are deactivated and a sensitized response cannot be elicited. Tolerance Nicotine CIS CGS + + + + Craving

  46. With deactivated receptors, acetylcholine is of no help in suppressing craving between cigarettes. Tolerance Acetylcholine CIS CGS + + + + Craving

  47. With heavy smoking, craving is suppressed when nicotine is present in high concentration. Tolerance Nicotine CIS CGS + + + + Craving

  48. Craving returns quickly when nicotine levels fall. Tolerance CIS CGS + + + + Craving

  49. What happens with cessation?

  50. 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

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