Imaging Nicotine- and Amphetamine-Induced Dopamine Release in Rhesus Monkeys with [11C]PHNO vs [11C]raclopride PET

The radiotracer [C-11]PHNO may have advantages over other dopamine (DA) D-2/D-3 receptor ligands because, as an agonist, it measures high-affinity, functionally active D-2/D-3 receptors, whereas the traditionally used radiotracer [C-11]raclopride measures both high- and low-affinity receptors. Our aim was to take advantage of the strength of [C-11]PHNO for measuring the small DA signal induced by nicotine, which has been difficult to measure in preclinical and clinical neuroimaging studies. Nicotine- and amphetamine-induced DA release in non-human primates was measured with [C-11]PHNO and [C-11]raclopride positron emission tomography (PET) imaging. Seven adult rhesus monkeys were imaged on a FOCUS 220 PET scanner after injection of a bolus of [C-11]PHNO or [C-11]raclopride in three conditions: baseline; preinjection of nicotine (0.1 mg/kg bolus + 0.08 mg/kg infusion over 30 min); preinjection of amphetamine (0.4 mg/kg, 5 min before radiotracer injection). DA release was measured as change in binding potential (BPND). Nicotine significantly decreased BPND in the caudate (7 +/- 8%), the nucleus accumbens (10 +/- 7%), and in the globus pallidus (13 +/- 15%) measured with [C-11]PHNO, but did not significantly decrease BPND in the putamen or the substantia nigra or in any region when measured with [C-11]raclopride. Amphetamine significantly reduced BPND in all regions with both radiotracers. In the striatum, larger amphetamine-induced changes were detected with [C-11]PHNO compared with [C-11]raclopride (52-64% vs 33-35%, respectively). We confirmed that [C-11]PHNO is more sensitive than [C-11]raclopride to nicotine- and amphetamine-induced DA release. [C-11]PHNO PET may be more sensitive to measuring tobacco smoking-induced DA release in human tobacco smokers.