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 [(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.