Occupancy of brain dopamine D3 receptors and drug craving: a translational approach

Abstract

Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.

Figures

Figure 1

(a) Increase of basal [35S]guanosine-5′-(γ-thio)triphosphate ([35S]GTPγS) binding to (hD3R)/inducible cell membranes by the agonist quinelorane, alone or in the presence of increasing concentrations of GSK598809. (b) Association of [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([125I]7OH-PIPAT) binding to rD3Rs/stable cell membranes, alone or in the presence of increasing concentrations of GSK598809. (c) Dissociation of [125I]7OH-PIPAT binding to rD3Rs/stable cell membranes induced by the addition of an excess of unlabeled ligand(s).

Figure 2

(a) Ex vivo [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([125I]7OH-PIPAT) binding to representative, coronal, one-hemisphere brain sections from rats treated with vehicle or GSK598809 (3 mg/kg, intraperitoneally (i.p.)). (b) Occupancy of [125I]7OH-PIPAT binding sites (=OD3R) in the rat shell of the nucleus accumbens (AcbSh) at increasing blood (● ng/ml) and brain (○ ng/g) GSK598809 concentrations, 1 h after administration of GSK598809 (0.05–3 mg/kg intraperitoneally). (c) Time–course of the OD3R in the rat AcbSh (●) after a single administration of GSK598809 (1 mg/kg intraperitoneally); the figure also shows GSK598809 concentration in the blood (dotted line; ng/ml) and brain (dashed line; ng/g).

Figure 3

Expression of nicotine-induced conditioned place preference (CPP) in rat and dose-dependent inhibition by GSK598809 at different pre-treatment times. (a) Pre-treatment time was 30 min (preference index (PI) values were calculated from data already reported in Micheli et al (2010)). (b) Pre-treatment time was 4 or 8 h, as shown in the figure. *, **, and ***P<0.01, 0.001, and 0.0001, respectively; U, unpaired rats.

Figure 4

Occupancy of in vivo [11C]-(+)-2H-naphth[1,2-b]-1,4-oxazin-9-ol, 3,4,4a,5,6,10b-hexahydro-4-propyl-([11C]PHNO) binding sites (OPHNO) in the baboon and human ventral striatum (VST) (a), globus pallidus (GP) (b), and substantia nigra (SN) (c) at increasing plasma GSK598809 concentrations (at the beginning of the scan), as revealed by positron emission tomography (PET) methodology (original values were partially already reported in Searle et al (2010)).