The behavioural and neurobiological effects of smoking are similar to those of other addictive substances [
1], and several studies have demonstrated the involvement of the mesolimbic dopaminergic system in mediating the response to cigarette smoking or nicotine intake. Nicotine-induced dopamine release has been demonstrated in rodents [
2‐
4] and non-human primates [
5‐
8]. These findings have been indirectly supported by several positron emission tomography (PET) studies where decreases of [
11C]raclopride binding (thought to reflect increases in the extracellular concentration of dopamine) in the ventral striatum/nucleus accumbens following smoking [
6,
9‐
12] or nicotine intake [
13] were observed. PET-studies, using radiopharmaceuticals for the dopamine D
2/3 receptors, have demonstrated significant associations between dopamine release and reduction in craving [
9,
10], enhancement of pleasure [
14,
15] and the severity of nicotine dependence [
12]. However, the reduction in D
2/
3 binding upon smoking compared to the baseline condition is modest (5% to 10%) in these studies compared to that following cocaine (20% to 30%) [
16] and amphetamine [
17‐
19]. Such an effect of 5% to 10% is similar to the test-retest variability of molecular imaging techniques using PET and SPECT [
20‐
22] and may be difficult to demonstrate in PET and SPECT studies using small data samples. This may explain the failure of some PET studies to demonstrate changes in [
11C]raclopride binding upon nicotine administration [
14,
15]. Dopamine release in the ventral striatum/nucleus accumbens has been demonstrated to be directly mediated through the binding of nicotine to α4β2 nAChRs leading to an increase in firing rate in dopamine neurons of the ventral tegmental area [
23,
24]. Previous human imaging studies do not provide strong support for the idea that postsynaptic dopamine D
2/
3 receptor availability is affected by chronic exposure to cigarette smoke. A reduced dopamine D
2/
3 receptor availability was demonstrated in the putamen in men [
25], but not in woman [
26]. Two SPECT studies failed to demonstrate changes in striatal dopamine D
2/
3 receptor availability in smokers compared to non-smokers [
27,
28].
The dopamine transporter (DAT) provides the primary mechanism through which dopamine is cleared from the extracellular fluid after its release from the presynaptic cell. However, only few studies have addressed the effect of chronic dosing of nicotine on the DAT [
29]. Nicotine is not a competitor nor a substrate for DAT [
30], and it does not bind to a site on the DAT protein [
31]. Nicotine appears to induce changes in DAT function by indirect mechanisms which include both augmentation (enhancing amphetamine-induced reverse transport of dopamine by DAT) and reduction (increase in cell surface DAT expression) of dopaminergic neurotransmission [
32]. Human imaging studies of DAT availability in relation to chronic tobacco smoking are sparse and have generated conflicting results [
28,
33] possibly related to methodological problems including the choice of radioligand and sample size. We studied the DAT availability using [
123I]FP-CIT-SPECT in a group of 26 active smokers, 39 ex-smokers and 64 subjects with no history of smoking. We tested the hypothesis that DAT availability is changed in active smokers compared to ex-smokers and subjects with no history of tobacco smoking. Understanding the mechanisms underlying the neurobiological effects of nicotine on the regulation of DAT may have the potential to translate into new and possibly individualized treatment strategies.