1. 11 Motivation  Nicotine causes DA release in the striatum, part of the mesolimbic DA pathway which mediates reinforcing behaviors (Martin-Soelch et al, 2001; Volkow et al, 2009).  Addictive liability may be dependent on timing of dopamine release (Volkow and Swanson, 2003). Varenicline has been hypothesized to work on the timing of DA release (Rollema et al, 2007).

2. 22 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/kg0.050mg/kg

3. 33 Smoking-induced DA release may be difficult to measure with PET  Doses of amphetamine that produced a 600% increase in DA only caused ~20% decrease in BP ND (Seneca et al, 2006).  Simulations suggest that at least a 200% increase in DA is necessary for a 5-10% decrease in [ 11 C]raclopride BP ND.

4. 4 Previous nicotine-induced DA studies with PET  Mixed results from previous [ 11 C]raclopride studies of nicotine-induced DA release.  Motion artifact? Study design? Insensitive outcome measure? This suggests that smoking-induced DA release may be difficult to detect reliably with typical PET methods.

5. 5 Specific Aims 1. Design an experiment that allows subjects to smoke while in the PET camera using advanced motion measurement and correction techniques to capture all aspects of smoking that may affect DA release. 2. Optimize ntPET techniques for analysis of smoking studies to measure time-varying DA release, parameters of which may determine addiction liability and treatment efficacy. 5

6. 66 Proposed study design  Scan smokers with B (n=4) or B/I (n=4) of [ 11 C]raclopride. Each subject will receive 2 scans on separate days (rest and smoking conditions).  Use Vicra optical tracking system to measure subject motion during scan.  Reconstruct dynamic scan data with MOLAR (Carson et al, 2003 ), incorporating motion information from the Vicra.  Subjects will smoke 3 cigarettes, spaced 25 min apart during the scan.  Freestanding ventilation and filter system to capture smoke.

7. 77 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

8. 88 Proposed analysis  Estimate BP ND by Logan reference method or SRTM.  Apply nonparametric neurotransmitter PET (np-ntPET) to estimate time-varying DA signal (Constantinescu et al, 2007, 2008). Singular value decomposition (SVD) based method to extract change in free DA concentration.  Apply HYPR (HighlY constrained backPRojection) (Christian et al, 2010). Image-processing strategy to improve SNR while preserving edges in TACs.  Investigate relationship between outcome measures (BP ND and F DA ) and behavioral data (FTND, years smoked, craving, nicotine high, etc).

9. 99 Preliminary Results  To date 6 subjects have successfully been scanned: 4 B, 2 B/I Rest Smoking

10. 10  ΔBP ND was calculated as and agrees with previous reports.  A significant negative correlation was found between ΔBP ND in the left dorsal caudate and FTND and a significant positive correlation was found between ΔBP ND in the right ventral striatum and # years smoking n = 6 n=5, p < 0.05