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

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 [ ¹¹ C]FLB457, a dopamine D ₂ /D ₃ receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [ ¹¹ 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. [ ¹¹ C]FLB457-binding potential (BP _ND ) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BP _ND after vs before amphetamine (Δ BP _ND ) 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 _ND from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [ ¹¹ C]FLB457 BP _ND 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.