Elevation of dopamine induced by cigarette smoking: novel insights from a [11C]-+-PHNO PET study in humans

Abstract

Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [(11)C]-(+)-PHNO ([(11)C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [(11)C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [(11)C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [(11)C]-(+)-PHNO binding in D2 and D3-rich areas (-12.0 and -15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [(11)C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.

Figure 1

Subjective reports at baseline, pre- and post-scan time points in abstinence (ABS) and smoking (NIC) condition: (a). Factor 2 score (Questionnaire of Smoking Urges, QSU). (b). Emotionality factor (Tobacco Craving Questionnaire, TCQ. (c). Expectancy factor (Tobacco Craving Questionnaire, TCQ). (d). Urge to Smoke (UTS). (e). Minnesota Nicotine Withdrawal Scale (MNWS). (f). State-trait anxiety inventory (STAI). Mean±S.E.M.; *condition effect, P<0.05; ^#pairwise Bonferroni-corrected comparison between the time points, P<0.05.

Figure 2

[¹¹C](+)PHNO BP_ND in abstinence (empty circles) and smoking condition (full circles) in selected ROIs (n=10, except for VP, n=9). Left y axis: SN, substantia nigra; AST, associative striatum; LST, limbic striatum; SMST, sensorimotor striatum; Right y axis: VP, ventral pallidum; *P<0.05.

Figure 3

T-statistical overlaid average T1 MRI showing clusters of significantly reduced [¹¹C]-+-PHNO BP_ND after smoking a cigarette. Greatest decreases in [¹¹C]-+-PHNO BP_ND cluster in the ventral part of the striatum and in the area that corresponds to the ventral pallidum (t max=10.3; p FEW-corrected=0.03, k=736; x=−28, y=−10, z=−4). For visualization purposes the image is threshold at a P<0.05 uncorrected.

Figure 4

Relationship between [¹¹C](+)PHNO BP_ND change in limbic striatum (LST), rate of smoking (puff number) and urge to smoke to relieve the negative affect (QSU/Factor 2; see in text for details on calculation). Pearson correlation coefficients (uncorrected r) and partial correlations coefficients (corrected r, controlling for the order of visits) are presented; *P<0.05.