Transcript Receptor in Baseline State

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