Title: Prevalence of Smoking in Psychiatric Disorders (PD) and Substance Abuse Disorders (SUD)
1Prevalence of Smoking in Psychiatric Disorders
(PD) and Substance Abuse Disorders (SUD)
Kalman D, Morrisette SB, and George, TP Am J
Addiction, 106-123, 2005
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3Nicotinic Acetylcholine Receptors (nAChR)
- Ligand gated ion channel
- Pentamer
- a and ß subunits
- Twelve known subunits a 2-10 and ß2-4
- Two main types present in brain
- a7 nAChR subtype
- High affinity for a- bungarotoxin
- a4ß2 nAChR subtype
- High affinity for nicotine
- Believed to upregulate in response to nicotine
4?2-nAChRs in the Reward Pathway
Dopamine
Nicotine
b2-nAChR
Ventral Tegmental Area
Ventral Striatum
5123I5-IA-85380 5-iodo-3-(2(S)-azetidinylmethox
y)pyridine
- High affinity for neuronal nAChRs
- High selectivity for nAChR with the ß2 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
6Subtype Selectivity of nAChR Ligands
Ligand Ki nM (Ratio to Ki(?4?2)) Ki nM (Ratio to Ki(?4?2)) Ki nM (Ratio to Ki(?4?2)) Ki nM (Ratio to Ki(?4?2))
Ligand ?4?2 ?3?4 ?7 muscle
()-Nicotine 0.84 (1) 100 (120) 130 (150) 1000 (1200)
(?)-Epibatidine 0.008 (1) 0.049 (6) 4.0 (500) 7.5 (900)
(?)-IPH 0.027 (1) 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 (1) 10.5 (420) 170 (6500) 460 (18000)
5-Iodo-A-85380 0.010 (1) 51 (5000) 250 (25000) 1400 (140000)
Mukhin, London et al. Mol. Pharmacol. 2000
7123I5-IA SPECT measurement of ?2-nAChR in
brain
(Staley et al., J Nuc Med, 2005)
8Evidence 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.
9Nicotine blocks 123I5-IA binding in nonhuman
primates
Urine cotinine levels (ng/mL) were measured with
NicoMeter test strips
(Staley et al., J Neuroscience 2006)
10Higher cortical ?2-nAChR in abstinent smokers
vs. never smokers
60
-
60
-
50
-
50
-
40
-
40
-
Never Smoker (Female, 31 yo)
30
-
30
-
20
-
20
-
10
-
10
-
Smoker (Female, 32 yo ), Abstinent 7 days
(Staley et al., J Neuroscience 2006)
11Evidence 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).
12The purpose was to examine ?2-nAChR availability
in tobacco smokers over the course of abstinence.
STUDY 1
- 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
13Abstinence 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)
Measured with NicAlert
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15123I5-IA SPECT regions of interest
AC
Anterior Cingulate
Medial FC
FC
Frontal Cortex
Cd
Caudate
Temporal Cortex
CB
TIC
Pt
Putamen
FC AC
FC AC
Th
Thalamus
PC
Parietal Cortex
Cerebellum
OC
Occipital Cortex
16Outcome 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.
17Subject Characteristics
1 day 1 wks 2 wks 4 wks 6-12 wks
N 7 17 7 11 6
Age 42.7 8.2 41.7 9.4 43.411.7 43.87.5 38.77.0
Days abstinent 1 7.71.4 17.93.0 30.54.2 69.023.5
Cigarettes smoked /day 19.910.2 19.78.5 22.77.9 14.73.6 20.310.3
Years Smoked 21.86.3 19.97.6 22.07.4 20.87.7 21.26.6
FTND 5.92.8 5.52.6 5.42.8 4.92.6 6.82.3
Urine cotinine (ng/mL) 790383 97.1236 91.461.2 9.111.4 30.040.6
Plasma cotinine (ng/mL) 370185 31.244.2 lt15 19.19.9 21.324.1
CO on scan day 12.07.2 3.22.4 2.91.9 2.92.2 4.23.3
18?2-nAChR availability in smokers normalizes over
the course of prolonged abstinence
Cosgrove..Staley, Arch Gen Psych, 2009
19?2-nAChR availability in brain during acute
abstinence
20?2-nAChR availability in brain during prolonged
abstinence
20 decrease from 1-12 wk
21?2-nAChR availability in brain over time in
abstinent smokers
22It takes up to 6-12 weeks for receptors to
normalize
23Negative 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
Staley et al., 2006
4 wks
Cerebellum
Cosgrove et al., 2009
24Summary Study 1
- Normalization of the nAChR..
- is prolonged in humans
- varies between individuals
- may be genetically-mediated