11

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

22

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.

0.00

5.00

10.00

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25.00

30.00

0 250 500 750 1000 1250

Dopamine Release (% of baseline)

De

cre

as

e in

Bin

din

g P

ote

nti

al (%

)

0

200

400

600

800

1000

1200

0 1000 2000 3000 4000 5000 6000Time (sec)

Dop

amin

e C

once

ntra

tion

(pm

ol/m

L)

3

Previous nicotine-induced DA studies with PET

Mixed results from previous [11C]raclopride studies of nicotine-induced DA release.

Motion artifact?

44

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

5

motion recorded during smoking 3 cigarettes

motion recorded during “baseline”

view from behind scanner real time view on monitor

66

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

77

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).

88

Preliminary Results

To date 6 subjects have successfully been scanned: 4 B, 2 B/I

0

0.5

1

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3.5

4

4.5

0 20 40 60 80 100 120 140

Time (minutes)

Co

nce

ntr

atio

n (

Bq

/mL

)

cerebellum

dorsal caudate

dorsal putamen

ventral striatum

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0.5

1

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Time (minutes)

Co

nce

ntr

atio

n (

Bq

/mL

)

cerebellum

dorsal caudate

dorsal putamen

ventral striatum

Rest

Smoking

9

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%

5%

10%

15%

20%

25%

30%

0 5 10 15 20 25 30 35 40 45

# 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%

4%

6%

8%

10%

0 1 2 3 4 5 6 7 8

FTND

ΔB

P ND

n=5, p < 0.05

n = 6

ΔB

PN

DΔ

BP

ND

years of smoking

FTND

VERY PRELIMINARY RESULTS

10

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