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.

Dopamine D3Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

“…In addition, a patient may take more drug than prescribed because of a missed a dose, seeking further relief from craving, or to accelerate recovery. In this study, doses of GSK598809 that resulted in exposure levels comparable to those reported in clinical trials (te Beek et al, 2012;Mugnaini et al, 2013) potentiated the hypertensive effects of cocaine. In addition, GSK598809 increased mean arterial blood pressure and heart rate at exposure levels encompassed by intent to treat dosages.…”

“…The cocaine doses increased blood pressure and were in a range sufficiently sensitive to reveal the potentiating effect of GSK598809. Plasma levels of GSK598809 in the animals were comparable to those observed in clinical trials using 75 and 175 mg GSK598809 to study its effects on cigarette craving (Mugnaini et al, 2013) and on interaction with alcohol (te Beek et al, 2012).…”

“…term5598809&Search5Search). One of these clinical studies, which focused on craving in smokers, reported that a single dose of GSK598809 that produced 72% to 89% dopamine D 3 receptor occupancy could transiently alleviate craving after overnight abstinence (Mugnaini et al, 2013). Hence, there are data on GSK598809 safety and kinetics in animals and in humans, and human plasma levels at potential intent-to-treat dosages.…”

Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys

“…There is evidence supporting the use of D3R antagonists and partial agonists for the treatment of cocaine and MA abuse as well as accompanying symptoms such as cognitive dysfunction (Newman et al, 2012;Mugnaini et al, 2013;Nakajima et al, 2013). Considering female rhesus monkeys in the current study were less sensitive to the behavioral effects of quinpirole, it is likely that drug potency will be a critical variable in future studies investigating D3R compounds as a treatment option.…”

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

“…It has also been reported that a year of voluntary alcohol drinking in alcohol preferring, in high alcohol drinking, and in Wistar rats was associated with an upregulation of DRD3 gene expression in the striatum (Vengeliene et al, 2006). Interestingly, in humans a single dose of a selective DRD3 antagonist was recently shown to partially alleviate cigarette craving in short-term abstinent smokers (Mugnaini et al, 2013).…”