nicotine causes dose-dependent release of da in the striatum
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Nicotine causes dose-dependent release of DA in the striatum
1 cigarette contains ~1mg nicotine which results in a ~0.014mg/kg dose to a 70kg human.
Dose-dependent IV nicotine-induced DA release in the rat nucleus accumbens (Pontiere et al, 1996)
0.025mg/kg 0.050mg/kg
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DA release measured via PET is a saturating signal
Doses of amphetamine that produced a 600% increase in DA only caused ~20% decrease in BPND (Seneca et al, 2006).
Simulations suggest that at least a 200% increase in DA is necessary for a 5-10% decrease in [11C]raclopride BPND.
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Dopamine Release (% of baseline)
De
cre
as
e in
Bin
din
g P
ote
nti
al (%
)
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0 1000 2000 3000 4000 5000 6000Time (sec)
Dop
amin
e C
once
ntra
tion
(pm
ol/m
L)
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Previous nicotine-induced DA studies with PET
Mixed results from previous [11C]raclopride studies of nicotine-induced DA release.
Motion artifact?
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Proposed study design
Each subject will receive 2 scans on separate days (rest and smoking conditions).
Vicra optical tracking system to measure subject motion during scan at 20Hz.
Reconstruct dynamic scan data with information from the Vicra.
Subjects will smoke 1 or more cigarettes during the scan.
Ventilation and filter system to capture smoke.
motion recorded during 2 SUCCESSIVE cigarettes
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motion recorded during smoking 3 cigarettes
motion recorded during “baseline”
view from behind scanner real time view on monitor
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Subjects/Eligibility
Men and women, aged 18-45 years
DSM-IV criteria for nicotine dependence via structured clinical interview diagnostic (SCID)
Fagerstrom Test for Nicotine Dependence (FTND) rating of at least 3
Using > 10 cigarettes per day for at least 1 year
CO levels > 10 ppm during intake evaluation
no exclusion for drinking alcohol
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Proposed analysis
Estimate BPND by Logan plot or SRTM.
Apply “ntPET” analysis to estimate time-varying DA signal (
Investigate relationship between outcome measures (BPND and FDA) and behavioral data (FTND, years smoked, craving, nicotine high, etc).
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Preliminary Results
To date 6 subjects have successfully been scanned: 4 B, 2 B/I
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Time (minutes)
Co
nce
ntr
atio
n (
Bq
/mL
)
cerebellum
dorsal caudate
dorsal putamen
ventral striatum
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Time (minutes)
Co
nce
ntr
atio
n (
Bq
/mL
)
cerebellum
dorsal caudate
dorsal putamen
ventral striatum
Rest
Smoking
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ΔBPND was calculated as
and agrees with previous reports.
Significant correlations were found between ΔBPND in the left dorsal caudate and FTND
and between ΔBPND in the right
ventral striatum and number of years of smoking
100Rest
Rest
ND
SmokeNDND
ND BP
BPBPBP
Region ΔBP ND
Left Dorsal Caudate 2 ± 4%Right Dorsal Caudate 5 ± 7%Left Dorsal Putamen 3 ± 8%Right Dorsal Putamen -1 ± 8%Left Ventral Striatum 0 ± 9%Right Ventral Striatum 8 ± 12%
Right Ventral Striatum
y = 0.009x - 0.1536
R2 = 0.7798
-15%
-10%
-5%
0%
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# Years Smoking
ΔB
P ND
n=5, p < 0.05
Left Dorsal Caudate
y = -0.0174x + 0.0987
R2 = 0.8046
-4%
-2%
0%
2%
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10%
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FTND
ΔB
P ND
n=5, p < 0.05
n = 6
ΔB
PN
DΔ
BP
ND
years of smoking
FTND
VERY PRELIMINARY RESULTS
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Model without dopamine change
Model with Dopamine change
Model-predicted dopamine response to smoking two cigarettes starting at 45 min.
Note: this is the response at a SINGLE voxel in the dorsal caudate.
Preliminary temporal analysis
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