Measuring cigarette smoking-induced cortical dopamine release: A [¹¹C]FLB-457 PET study

Abstract

Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [(11)C]-FLB-457-binding potential (BPND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BPND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BPND change -12.1±9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [(11)C]FLB-457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response.

Figure 1

Single subject timeline.

Figure 2

[11C]FLB-457-binding potential (BP_ND) in abstinence and smoking conditions (n=10). (a) Clusters surviving a threshold of P<0.05 (uncorrected)/k>50 for the abstinence>smoking contrast. Clusters identified in the insula, amygdala, cingulate, and prefrontal cortex (PFC) are overlaid onto a single subject T1-weighted magnetic resonance imaging (MRI; in MNI space). Coordinates below each view are in MNI space. (b) Extracted [11C]FLB-457 BP_ND values for significant clusters in the voxel-wise comparison of abstinent (open circles) and smoking conditions (closed circles). ACC, anterior cingulate gyrus; L, left; Med. FG, medial frontal gyrus; MPFC, medial PFC; R, right.