Nicotine Dependence Begins with the First Cigarette
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Transcript of 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
Nicotine Dependence Begins with the First Cigarette
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
CGS The Craving Generation
SystemCraving
The Sensitization-Homeostasis Model
CIS CGSThe Craving Inhibition System
Craving
The Sensitization-Homeostasis Model
CIS CGS
Acetylcholine (Stimulatory)
Craving
The Sensitization-Homeostasis Model
CIS CGSDopamine (Inhibitory)
Acetylcholine (Stimulatory)
Craving
The Sensitization-Homeostasis Model
CIS CGSDopamine (Inhibitory)
Acetylcholine (Stimulatory)
Craving
With intermittent smoking, nicotine acts on up-regulated receptors and produces a sensitized response.
CIS CGSNicotine
CGS
The sensitized response produces super-physiologic inhibition of the CGS
CIS CGSNicotine
SensitizedResponse
Super-physiologic inhibition of the CGS provokes homeostatic adaptations which increase activity in the CGS
CIS CGSNicotine
Homeostatic Adaptations
+ ++ +
The homeostatic adaptations cause the CGS to become autonomous, producing craving when it is not inhibited.
CIS CGSCraving
The Loss of Autonomy
+ ++ +
What causes nicotine withdrawal?
Withdrawal:Unopposed Homeostatic Adaptations
CGSCraving
Irritability
Difficulty Concentrating
+ +
+ + + +
+ +
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.
CIS CGS
Acetylcholine
Craving
Up-regulated Receptors
+ +
+ +
Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors.
CIS CGS
Acetylcholine
Craving
Up-regulated Receptors
+ +
+ +
Between cigarettes, the impact of acetylcholine is magnified by the up-regulation of receptors.
CIS CGS
Acetylcholine
Craving
Up-regulated Receptors
+ +
+ +
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.
CIS CGS
Acetylcholine
+ +
+ +
Repeated inhibition provokes more permanent homeostatic adaptations to stimulate the CGS.
CIS CGS
AcetylcholineTolerance
+ +
+ +
CIS CGS
Acetylcholine
Craving
Tolerance
With this additional stimulation to the CGS, acetylcholine is no longer sufficient to inhibit craving between cigarettes.
+ +
+ +
CIS CGS
Nicotine
Craving
Tolerance
The smoker begins to smoke more frequently to suppress craving.
+ +
+ +
CIS CGS
Nicotine
Craving
Tolerance
Sensitized Response to Nicotine
When cigarettes are spaced a day apart, a sensitized response is obtained...
+ +
+ +
CIS CGS
Nicotine
Craving
Tolerance
…and craving is temporarily blocked.
+ +
+ +
Tolerance strengthens slowly over time, prompting more frequent smoking.
CIS CGS
Nicotine
Craving
Tolerance
+ +
+ +
When use exceeds one cigarette per day, receptors are deactivated and a sensitized response cannot be elicited.
CIS CGS
NicotineTolerance
Craving+ +
+ +
With deactivated receptors, acetylcholine is of no help in suppressing craving between cigarettes.
CIS CGS
AcetylcholineTolerance
Craving+ +
+ +
With heavy smoking, craving is suppressed when nicotine is present in high concentration.
CIS CGS
NicotineTolerance
Craving+ +
+ +
Craving returns quickly when nicotine levels fall.
CIS CGS
Tolerance
Craving+ +
+ +
What happens with cessation?
Within 24 hours receptors become reactivated, but acetylcholine is too weak to inhibit craving after tolerance
has developed.
CIS CGS
Acetylcholine
Craving is intense
Tolerance
+ +
+ +
The homeostatic adaptations within the CGS begin to fade immediately.
CIS CGS
Acetylcholine
Craving becomes less
intense
Tolerance
+
Within a month, receptors have down-regulated, restoring inhibition of the CGS to non-smoker levels.
CIS CGSCraving
Tolerance
Acetylcholine
Stimulation from tolerance continues to produce craving.
Homeostatic adaptations develop to oppose the constant stimulation provided by tolerance.
CIS CGSCraving
Tolerance
Acetylcholine
The CGS is in balance. Craving is blocked.
+ +
+ +
Why does a single cigarette cause a relapse?
A single dose of nicotine causes a sensitized response.
CIS CGSCraving
Tolerance
Nicotine
+ +
+ +
A single dose of nicotine causes a sensitized response.
CIS CGSCraving
Tolerance
Nicotine
+ +
+ +
The resulting super-physiologic inhibition of the CGScauses the inhibitory homeostatic adaptations to disappear.
CIS CGSCraving
Tolerance
Tolerance causes an immediate resumption of strong craving.
CIS CGSCraving
Tolerance
Funded by
The National Institute on Drug Abuse
Nicotine Dependence Begins with the First Cigarette