Prevalence of Smoking in Psychiatric
Disorders (PD) and Substance Abuse
Disorders (SUD)
Kalman D, Morrisette SB, and George, TP Am J Addiction, 106-123, 2005
Nicotinic Acetylcholine Receptors
(nAChR)
•Ligand gated ion channel
•Pentamer
•α and β subunits
•Twelve known subunits α 2-10 and
β2-4
•Two main types present in brain
•α7 nAChR subtype
•High affinity for αbungarotoxin
•α4β2 nAChR subtype
•High affinity for nicotine
•Believed to upregulate in
response to nicotine
2*-nAChRs in the Reward Pathway
Dopamine
Nicotine
2-nAChR
Ventral Tegmental Area
Ventral Striatum
[123I]5-IA-85380
[5-iodo-3-(2(S)-azetidinylmethoxy)pyridine]
•
•
•
•
•
•
High affinity for
neuronal nAChRs
High selectivity for
nAChR with the β2
subunit
Low nonspecific binding
Dissociates slowly from
the receptor
Readily crosses the
blood brain barrier
Low toxicity
Musachio 1998, 1999; Fujita 2000; Horti 1999; Mukhin 2000
Subtype Selectivity of nAChR Ligands
Ki nM (Ratio to Ki(42))
Ligand
(–)-Nicotine
42
34
7
muscle
0.84
100
130
1000
(1)
(120)
0.008
0.049
(6)
(500)
(900)
0.027
0.11
(4)
30
(1100)
6.5
(240)
2-Fluoro-A-85380
0.046
(1)
110
(2400)
165
(3600)
360
(7800)
6-Fluoro-A-85380
0.025
10.5
(420)
170
(6500)
460
(18000)
5-Iodo-A-85380
0.010
51
250
1400
()-Epibatidine
()-IPH
(1)
(1)
(1)
(1)
(5000)
(150)
4.0
(25000)
(1200)
7.5
(140000)
Mukhin,… London et al. Mol. Pharmacol. 2000
[123I]5-IA SPECT measurement of
2*-nAChR in brain
Thal am us
C o rtex
C e r e be l l um
St r i at um
20
15
15
10
10
5
5
123
R e g io n a l [ I]5-IA
U pta ke [kB q /c c]
20
0
0
2
123
6
To tal P ar e nt
0 .4
[ I]5-IA P lasm a
A ctiv ity [kB q/cc]
4
8
10
F r e e P ar e nt
4
6
8
2
4
6
8
0 .4
0 .3
0 .3
0 .2
0 .2
0 .1
0 .1
0 .0
2
0 .0
2
4
6
8
10
(Staley et al., J Nuc Med, 2005)T im e (h)
T ime (h)
Evidence nAChRs upregulate
• Nicotine, the primary addictive chemical in tobacco smoke,
upregulates the nicotinic acetylcholine receptor (nAChR).
• This has been shown postmortem in human tobacco
smokers (Breese et al., 1997; Court et al., 1998).
• Confirmed in animal studies after chronic nicotine exposure
(Kassiou et al., 2001, Marks et al., 1992).
• Due to changes in receptor density, Bmax, as opposed to
changes in receptor affinity, KD (Peng et al., 1994; Marks et al.,
1983).
• The changes in receptor density may underlie tobacco
smoking tolerance and dependence.
Nicotine blocks [123I]5-IA binding in nonhuman primates
I ]5 -I A U p ta k e
V T'
150
150
Salem
100
100
thalamus
CC
FC
OC
BG
W inston
123
> 10,000
50
50
5-10,000
0
1000-2000
(Staley
et al., J Neuroscience 2006)
0
[
2000-5000
Urine cotinine levels (ng/mL)
were measured with
NicoMeter™ test strips
W i nsto n
Higher cortical 2*-nAChR in
abstinent smokers vs. never smokers
605040-
Never Smoker (Female, 31 yo)
30
30-
2010-
Smoker (Female, 32 yo ), Abstinent 7 days
[
123
I ] 5- I A U p t ak e V
T'
80
Tha la m us
4 0 Stri atum
4 0 Co rtex
p = 0.0004
p=0.0001
4 0 C erebel l um
p = 0.014
60
30
30
30
40
20
20
20
20
10
10
10
(Staley et al., J Neuroscience
2006)
Evidence nAChRs normalize over time
Preclinical: nicotine binding returns to control levels
between 7 days and 3 weeks abstinence depending on
the route of administration and dosing regimen
(Marks et al., 1985; Pietila et al., 1998; Ksir et al., 1985).
Postmortem: smokers who quit at least 2 months prior
to death had nicotine binding levels similar to
controls (Breese et al., 1997).
In vivo: the upregulation was shown to be temporary,
decreasing by 21 days of abstinence (Mamede et al.,
2007).
STUDY 1
The purpose was to examine
2*-nAChR availability in
tobacco smokers over the
course of abstinence.
Smokers were scanned up to 4 times…..
1 week, 4 weeks, 6-12 weeks
1 day, 1 week, 2 weeks, 4 weeks
Cosgrove…..Staley, Arch Gen Psych, 2009
Abstinence from smoking
Smokers were helped to remain abstinent with
contingency management techniques. Abstinence was
confirmed twice daily for the first 8 days with carbon
monoxide and urine cotinine measurements.
Urine Cotinine levels
(ng/mL)
Carbon monoxide
levels (ppm)
50
40
>1000
5 0 0 -1 0 0 0
2 0 0 -5 0 0
30
1 0 0 -2 0Measured
0
with NicAlert™
1. Radiotracer Synthesis
MRI & SPECT
1)
M e 3 Sn
O
3. Metabolism &
protein binding
I /Cl-T
123
N
Boc
N
123 -
I
O
NH
2) HCl/Et2 O
N
2. Radiotracer
Injection
4. SPECT &
STEP Scan
MRI
SPECT
[123I]5-IA SPECT regions of interest
FC
Frontal
Cortex
Medial FC
AC
Anterior Cingulate
Cd
Caudate
Temporal
TIC
Cortex
PC
Parietal Cortex
FC AC
Pt
Putamen
CB
Th
Thalamus
OC
Occipital Cortex
Cerebellum
Outcome Measure
VT/fp = radioactivity in brain /blood
Receptor “availability”
• Receptors that are free or available to be
bound by the radiotracer.
• It is not a measure of all receptors,
because some could be occupied by
acetylcholine or nicotine.
Subject Characteristics
1 day
~1 wks
~2 wks
~4 wks
6-12 wks
N
7
17
7
11
6
Age
42.7+ 8.2
Days abstinent
1
7.7+1.4
17.9+3.0
30.5+4.2
69.0+23.5
# Cigarettes
smoked /day
19.9+10.2
19.7+8.5
22.7+7.9
14.7+3.6
20.3+10.3
# Years Smoked
21.8+6.3
19.9+7.6
22.0+7.4
20.8+7.7
21.2+6.6
FTND
5.9+2.8
5.5+2.6
5.4+2.8
4.9+2.6
6.8+2.3
Urine cotinine
(ng/mL)
790+383
97.1+236 91.4+61.2 9.1+11.4
30.0+40.6
Plasma cotinine
(ng/mL)
370+185
31.2+44.2
<15
19.1+9.9
21.3+24.1
CO on scan day
12.0+7.2
3.2+2.4
2.9+1.9
2.9+2.2
4.2+3.3
41.7+ 9.4 43.4+11.7 43.8+7.5
38.7+7.0
2*-nAChR availability in smokers normalizes
over the course of prolonged abstinence
Cosgrove…..Staley, Arch Gen Psych, 2009
2*-nAChR availability in brain
during acute abstinence
2*-nAChR availability in brain
during prolonged abstinence
20%
decrease
from 1-12 wk
2*-nAChR availability in brain
over time in abstinent smokers
It takes up to 6-12 weeks for
receptors to “normalize”
160-
Nonsmokers
Smokers
1 Day
Smokers
1 Week
Smokers
2 Weeks
Smokers
4 Weeks
Smokers
6-12 Weeks
125-
90-
55-
20-
Negative correlation between 2*nAChR availability and craving
Relief of Negative Affect or Withdrawal/Urge to smoke
1 wk
Correlate
Region
Cluster
size
T statistic
r value
p
value
Craving
Parietal Cortex
Postcentral Gyrus
BA43
311
7.18
0.93
0.016
4 wks
Staley et al., 2006
Cerebellum
Cosgrove et al., 2009
Summary Study 1
Normalization of the nAChR……..
– is prolonged in humans
– varies between individuals
– may be genetically-mediated