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

Abstract

Selective dopamine D3 receptor (D3R) 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 3R 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 D3 Rs (OD3R) 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 (125I7OH-PIPAT) autoradiography and 11CPHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D3 Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between OD3R 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 OD3R at every time point, and 100% effect at OD3R values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of OD3R, transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O D3R 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 D3R antagonist for the treatment of substance-use disorders. © 2013 American College of Neuropsychopharmacology. All rights reserved.