title: 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.
authors.affiliation: GlaxoSmithKline (GSK) Medicines Research Centre, Verona, Italy. manolo.mugnaini@aptuit.com
authors.forename: Manolo
authors.initials: M
authors.lastname: Mugnaini
authors.forename: Laura
authors.initials: L
authors.lastname: Iavarone
authors.forename: Palmina
authors.initials: P
authors.lastname: Cavallini
authors.forename: Cristiana
authors.initials: C
authors.lastname: Griffante
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oliosi
authors.forename: Chiara
authors.initials: C
authors.lastname: Savoia
authors.forename: John
authors.initials: J
authors.lastname: Beaver
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Micheli
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
authors.forename: Anne
authors.initials: A
authors.lastname: Andorn
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo Pich
authors.forename: Massimo
authors.initials: M
authors.lastname: Bani
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D048530:Papio anubis; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012907:Smoking / Q000188:drug therapy* / Q000378:metabolism*; D016540:Smoking Cessation / Q000379:methods; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3