Objectives
Recently changes in receptor density (Bmax) and dissociation constant (KD) were reported to explain all of the observed decreases in binding potential (BP) after amphetamine challenge. In this report, we estimated the occupancy (O-amph) and synaptic concentration (C-amph) of amphetamine-derived DA assuming no changes in Bmax and KD (a competition model) to speculate whether the BP changes were in fact explained by occupancy changes.
Methods
Eight healthy subjects (age: 25 ± 6) were studied with PET for 90 min following a bolus injection of [11C]raclopride. Each subject underwent one high specific activity scan under a baseline (HSA-B), one HSA scan following i.v. amphetamine (0.3 mg/kg; HSA-A), and one low specific activity baseline scan (LSA-B). Radioactivity time-profiles were obtained for anterior (ant-) and posterior (post-) putamen (Pu) and caudate nucleus (CN), ventral striatum (VS), and cerebellum (Cb). Regional estimates of BP were obtained by the bolus-plus-infusion transformation (BPIT) approach (NeuroImage 22: T81 & T117) using Cb as a reference region, together with bound raclopride (B-rac in pmol/ml) in HSA-B and LSA-B scans. Regional Bmax and KD were obtained by the Eadie-Hofstee plot: B = −BP·KD + Bmax where B is the sum of bound baseline DA (B-base, assumed a 10% occupancy) and B-rac. The total bound of the HSA-A scan (B) was obtained by inserting observed BP to the plot. Then, bound amphetamine-derived DA (B-amph) was obtained by subtracting B-base and B-rac from B. The occupancy by amphetamine-derived DA was obtained by dividing B-amph by Bmax. Finally the synaptic concentrations of baseline and amphetamine-derived DA (C-base and C-amph) were obtained using the following equation after a modification: O = C / (KD + C). Separately amphetamine induced DA release (DAR) was calculated as follows: (BPbase – BPamph)/BPbase·100 (%).
Results
Regional estimates of Bmax, KD, occupancy by amphetamine-derived DA, intra-synaptic concentrations of baseline and amphetamine-derived DA are listed in the Table 1. Amphetamine induced increases in intra-synaptic DA ranged from 61% (ant-CN) to 159% (post-Pu).
Regional values of the competition model (Assuming a 10% base line DA occupancy)
Conclusions
This study indicated that synaptic DA increased modestly (<200%) following amphetamine challenge when a 10% baseline DA occupancy was assumed. The magnitudes were consistent with the several fold-increase in extracellular DA reported in microdialysis studies in non-human primates. Thus, we conclude that a competition model may be able to describe changes in DA kinetics without assuming changes in Bmax and KD in acute amphetamine challenge.