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