The Effect of Treatment with Guanfacine, an Alpha2 Adrenergic Agonist, on Dopaminergic Tone in Tobacco Smokers: An [11C]FLB457 PET Study

Abstract

Guanfacine, a noradrenergic alpha2a agonist, reduced tobacco smoking in a 4-week trial and in animal models has been shown to reduce cortical dopamine release, which is critically involved in the reinforcing effect of tobacco smoking. We measured amphetamine-induced extrastriatal dopamine release before and after treatment with guanfacine with [C]FLB457, a dopamine D/D receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [C]FLB457 PET scans on the same day, one before and one at 2.5-3 h after amphetamine (0.4-0.5 mg/kg, PO). A subset (n=12) then underwent guanfacine treatment (3 mg/day for 3 weeks) and the set of scans were repeated. [C]FLB457-binding potential (BP) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BP after vs before amphetamine (Δ BP) is an indirect measure of DA release and was compared between the untreated and guanfacine-treated conditions. Guanfacine treatment attenuated amphetamine-induced DA release; however, the change was due to a global 8% decrease in baseline BP from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [C]FLB457 BP in tobacco smokers, suggesting an increase in dopaminergic tone. Guanfacine-induced normalization of dopamine signaling may be an important mesocortical mechanism contributing to its ability to aid in tobacco smoking cessation.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

“…Supplementary Table 3 also includes more extensive methodological details, such as PET camera, number of males and females, modeling method, reference region, scan length and modeling notes. Asterisks indicate transporters Receptor/transporter Neurotransmitter Tracer Measure n Age References D 1 Dopamine [ 11 C]SCH23390 BP ND 13 (7) 33 ± 13 Kaller et al 58 D 2 Dopamine [ 11 C]FLB-457 BP ND 37 (20) 48.4 ± 16.9 Smith et al 59 , 60 D 2 Dopamine [ 11 C]FLB-457 BP ND 55 (29) 32.5 ± 9.7 Sandiego et al 59 – 63 DAT * Dopamine [ 123 I]-FP-CIT SUVR 174 (65) 61 ± 11 Dukart et al 64 NET * Norepinephrine [ 11 C]MRB BP ND 77 (27) 33.4 ± 9.2 Ding et al 65 – 68 5-HT 1A Serotonin [ 11 C]WAY-100635 BP ND 35 (17) 26.3 ± 5.2 Savli et al 69 5-HT 1B Serotonin [ 11 C]P943 BP ND 65 (16) 33.7 ± 9.7 Gallezot et al 70 – 76 5-HT 1B Serotonin [ 11 C]P943 BP ND 23...…”

Failure to detect amphetamine‐induced dopamine release in the cortex with [11C]FLB 457 positron emission tomography (PET): Methodological considerations

“…This analysis was conducted because, in a recent report, amphetamine-induced displacement of [ 11 C]FLB 457 BP ND was detected with SRTM, but not kinetic analyses (Sandiego et al, 2015). The inability to displace [ 11 C]FLB 457 BP ND in the cortex following an oral amphetamine challenge was unexpected, because three independent groups have replicated this observation in five different cohorts of healthy controls ( Table 5) (Narendran et al, 2009; Narendran et al, 2014; Sandiego et al, 2015; Sandiego et al, 2017; Slifstein et al, 2015). The scanning of subjects with [ 11 C]NPA before [ 11 C]FLB 457 in the amphetamine PET studies allowed for us to contrast ΔBP ND in the striatum with that in the cortex.…”

“…This result also has implications for longitudinal studies that have used [ 11 C]FLB 457 and amphetamine to measure dopamine release on two different days. For example, a recent study that documented amphetamine-induced displacement of [ 11 C]FLB 457 before and after three weeks of guanfacine treatment reported that guanfacine led to a decrease in dopamine release (∆BP ND ) (Sandiego et al, 2017). However, the smaller ∆BP ND measured in the guanfacine-treated relative to the untreated condition was attributable to a non-significant 4–12% decrease in baseline (not post-amphetamine) BP ND after chronic guanfacine treatment.…”

“…[ 11 C]FLB 457 is high affinity dopamine D 2/3 antagonist radiotracer that allows the for measurement of D 2/3 receptors in extrastriatal regions with relatively low receptor density (Halldin et al, 1995). Studies in healthy humans by three independent groups have demonstrated an 8–15% reduction in [ 11 C]FLB 457 BP ND (i.e., binding potential relative to non-displaceable uptake) in cortical regions following a 0.5 g kg −1 oral amphetamine challenge (Narendran et al, 2009; Narendran et al, 2014; Sandiego et al, 2015; Sandiego et al, 2017; Slifstein et al, 2015). This observation in healthy subjects has recently been contrasted with the inability to displace [ 11 C]FLB 457 in patients with schizophrenia and alcohol dependence, and is interpreted as a decrease in cortical dopamine transmission in these disorders (Narendran et al, 2014; Slifstein et al, 2015).…”

Cannabinoid receptor availability modulates the magnitude of dopamine release in vivo in the human reward system: A preliminary multitracer positron emission tomography study

“…Several brain positron emission tomography (PET) imaging studies have investigated DA release following an amphetamine (AMPH) challenge both in the striatum 4–8 and in the cortex 9–13 . Overall, these studies found that striatal DA signalling is related to positive rewarding effects, such as euphoria and drug wanting.…”